|
1
|
Liu B, Yi D, Li S, Ramirez K, Xia X, Cao Y, Zhao H, Tripathi A, Qiu S, Kala M, Rafikov R, Gu H, de Jesus Perez V, Lemay SE, Glembotski CC, Knox KS, Bonnet S, Kalinichenko VV, Zhao YY, Fallon MB, Boucherat O, Dai Z. Single-Cell and Spatial Transcriptomics Identified Fatty Acid-Binding Proteins Controlling Endothelial Glycolytic and Arterial Programming in Pulmonary Hypertension. Arterioscler Thromb Vasc Biol 2025. [PMID: 40401371 DOI: 10.1161/atvbaha.124.321173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 05/09/2025] [Indexed: 05/23/2025]
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for patients with PAH. Recent studies showed that FABP (fatty acid-binding protein) 4 and FABP5 are expressed in endothelial cells (ECs) across multiple tissues, and circulating FABP4 level is elevated in patients with PAH. However, the role of endothelial FABP4/5 in the pathogenesis of PAH remains undetermined. METHODS FABP4/5 expression was examined in pulmonary arterial ECs and lung tissues from patients with idiopathic PAH and pulmonary hypertension (PH) rat models. Plasma proteome analysis was performed in human PAH samples. Echocardiography, hemodynamics, histology, and immunostaining were performed to evaluate the lung and heart PH phenotypes in Egln1Tie2Cre (CKO) mice and Egln1Tie2Cre/Fabp4/5-/- (TKO) mice. Bulk RNA sequencing (RNA-seq), single-cell RNA sequencing analysis, and spatial transcriptomic analysis were performed to understand the cellular and molecular mechanisms of endothelial FABP4/5-mediated PAH pathogenesis. RESULTS Both FABP4 and FABP5 were highly induced in ECs of CKO mice and pulmonary arterial ECs from patients with idiopathic PAH (IPAH) and in whole lungs of PH rats. Plasma levels of FABP4/5 were upregulated in patients with IPAH and directly correlated with severity of hemodynamics and biochemical parameters. Genetic deletion of both Fabp4 and Fabp5 in CKO mice caused a reduction of right ventricular systolic pressure and right ventricular hypertrophy, attenuated pulmonary vascular remodeling, and prevented the right heart failure secondary to PH. FABP4/5 deletion also normalized EC glycolysis and distal arterial programming, reduced reactive oxygen species and HIF (hypoxia-inducible factor)-2α expression, and decreased aberrant EC proliferation in CKO lungs. CONCLUSIONS PH causes aberrant expression of FABP4/5 in pulmonary ECs, which leads to enhanced EC glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.
Collapse
Affiliation(s)
- Bin Liu
- Division of Pulmonary, Critical Care and Sleep, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., K.S.K., Z.D.)
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
- Translational Cardiovascular Research Center, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., C.C.G., Z.D.)
- Division of Pulmonary Critical Care and Medicine, Department of Medicine, Washington University School of Medicine in St. Louis, Saint Louis, MO (B.L., A.T., Z.D.)
| | - Dan Yi
- Division of Pulmonary, Critical Care and Sleep, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., K.S.K., Z.D.)
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
- Translational Cardiovascular Research Center, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., C.C.G., Z.D.)
| | - Shuai Li
- Division of Pulmonary, Critical Care and Sleep, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., K.S.K., Z.D.)
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
- Now with GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, China (S.L.)
| | - Karina Ramirez
- Division of Pulmonary, Critical Care and Sleep, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., K.S.K., Z.D.)
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
| | - Xiaomei Xia
- Division of Pulmonary, Critical Care and Sleep, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., K.S.K., Z.D.)
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
| | - Yanhong Cao
- Division of Pulmonary, Critical Care and Sleep, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., K.S.K., Z.D.)
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
| | - Hanqiu Zhao
- Division of Pulmonary, Critical Care and Sleep, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., K.S.K., Z.D.)
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
| | - Ankit Tripathi
- Division of Pulmonary, Critical Care and Sleep, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., K.S.K., Z.D.)
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
- Division of Pulmonary Critical Care and Medicine, Department of Medicine, Washington University School of Medicine in St. Louis, Saint Louis, MO (B.L., A.T., Z.D.)
| | - Shenfeng Qiu
- Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix. (S.Q.)
- Division of Pulmonary Critical Care and Medicine, Department of Medicine, Washington University School of Medicine in St. Louis, Saint Louis, MO (B.L., A.T., Z.D.)
| | - Mrinalini Kala
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
| | - Ruslan Rafikov
- Department of Medicine, Indiana University College of Medicine, Indianapolis (R.R.)
| | - Haiwei Gu
- College of Health Solutions, Arizona State University, Phoenix (H.G.)
| | - Vinicio de Jesus Perez
- Division of Pulmonary and Critical Care, Stanford University, Palo Alto, CA (V.d.j.P., O.B.)
| | - Sarah-Eve Lemay
- Pulmonary Hypertension and Vascular Biology Research Group, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada (S.-E.L., S.B.)
| | - Christopher C Glembotski
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
- Translational Cardiovascular Research Center, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., C.C.G., Z.D.)
| | - Kenneth S Knox
- Division of Pulmonary, Critical Care and Sleep, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., K.S.K., Z.D.)
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
| | - Sebastien Bonnet
- Pulmonary Hypertension and Vascular Biology Research Group, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada (S.-E.L., S.B.)
| | - Vladimir V Kalinichenko
- Phoenix Children's Health Research Institute, College of Medicine-Phoenix, University of Arizona, Phoenix. (V.V.K.)
- Division of Neonatology, Phoenix Children's Hospital, Phoenix, AZ (V.V.K.)
| | - You-Yang Zhao
- Program for Lung and Vascular Biology and Section for Injury Repair and Regeneration Research, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, IL (Y.-Y.Z.)
- Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL (Y.-Y.Z.)
| | - Michael B Fallon
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
| | - Olivier Boucherat
- Division of Pulmonary and Critical Care, Stanford University, Palo Alto, CA (V.d.j.P., O.B.)
| | - Zhiyu Dai
- Division of Pulmonary, Critical Care and Sleep, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., K.S.K., Z.D.)
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., S.L., K.R., X.X., Y.C., H.Z., A.T., M.K., C.C.G., K.S.K., M.B.F., Z.D.)
- Translational Cardiovascular Research Center, College of Medicine-Phoenix, University of Arizona, Phoenix. (B.L., D.Y., C.C.G., Z.D.)
| |
Collapse
|
|
2
|
Pasut A, Lama E, Van Craenenbroeck AH, Kroon J, Carmeliet P. Endothelial cell metabolism in cardiovascular physiology and disease. Nat Rev Cardiol 2025:10.1038/s41569-025-01162-x. [PMID: 40346347 DOI: 10.1038/s41569-025-01162-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2025] [Indexed: 05/11/2025]
Abstract
Endothelial cells are multifunctional cells that form the inner layer of blood vessels and have a crucial role in vasoreactivity, angiogenesis, immunomodulation, nutrient uptake and coagulation. Endothelial cells have unique metabolism and are metabolically heterogeneous. The microenvironment and metabolism of endothelial cells contribute to endothelial cell heterogeneity and metabolic specialization. Endothelial cell dysfunction is an early event in the development of several cardiovascular diseases and has been shown, at least to some extent, to be driven by metabolic changes preceding the manifestation of clinical symptoms. Diabetes mellitus, hypertension, obesity and chronic kidney disease are all risk factors for cardiovascular disease. Changes in endothelial cell metabolism induced by these cardiometabolic stressors accelerate the accumulation of dysfunctional endothelial cells in tissues and the development of cardiovascular disease. In this Review, we discuss the diversity of metabolic programmes that control endothelial cell function in the cardiovascular system and how these metabolic programmes are perturbed in different cardiovascular diseases in a disease-specific manner. Finally, we discuss the potential and challenges of targeting endothelial cell metabolism for the treatment of cardiovascular diseases.
Collapse
Affiliation(s)
- Alessandra Pasut
- Laboratory of Angiogenesis & Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Eleonora Lama
- Laboratory of Angiogenesis & Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Amaryllis H Van Craenenbroeck
- Division of Nephrology, University Hospitals Leuven, Leuven, Belgium
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Jeffrey Kroon
- Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
- Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischaemic Syndromes, Amsterdam, The Netherlands.
| | - Peter Carmeliet
- Laboratory of Angiogenesis & Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
| |
Collapse
|
|
3
|
Edwards DN, Wang S, Kane K, Song W, Kim LC, Ngwa VM, Hwang Y, Ess K, Boothby MR, Chen J. Increased fatty acid delivery by tumor endothelium promotes metastatic outgrowth. JCI Insight 2025; 10:e187531. [PMID: 40198126 DOI: 10.1172/jci.insight.187531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 03/27/2025] [Indexed: 04/10/2025] Open
Abstract
Metastatic outgrowth in distant microscopic niches requires sufficient nutrients, including fatty acids (FAs), to support tumor growth and to generate an immunosuppressive tumor microenvironment (TME). However, despite the important role of FAs in metastasis, the regulation of FA supply in metastatic niches has not been defined. In this report, we show that tumor endothelium actively promotes outgrowth and restricts antitumor cytolysis by transferring FAs into developing metastatic tumors. We describe a process of transendothelial FA delivery via endosomes that requires mTORC1 activity. Thus, endothelial cell-specific targeted deletion of Raptor (RptorECKO), a unique component of the mTORC1 complex, significantly reduced metastatic tumor burden that was associated with improved markers of T cell cytotoxicity. Low-dose everolimus that selectively inhibited endothelial mTORC1 improves immune checkpoint responses in metastatic disease models. This work reveals the importance of transendothelial nutrient delivery to the TME, highlighting a future target for therapeutic development.
Collapse
Affiliation(s)
- Deanna N Edwards
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
| | - Shan Wang
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kelby Kane
- Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA
| | - Wenqiang Song
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Medicine, Division of Epidemiology, and
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Laura C Kim
- Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Verra M Ngwa
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Yoonha Hwang
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kevin Ess
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mark R Boothby
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, Tennessee, USA
| | - Jin Chen
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
- Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, Tennessee, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
- Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| |
Collapse
|
|
4
|
Liu Y, Wu Z, Li Y, Chen Y, Zhao X, Wu M, Xia Y. Metabolic reprogramming and interventions in angiogenesis. J Adv Res 2025; 70:323-338. [PMID: 38704087 PMCID: PMC11976431 DOI: 10.1016/j.jare.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/30/2024] [Accepted: 05/01/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Endothelial cell (EC) metabolism plays a crucial role in the process of angiogenesis. Intrinsic metabolic events such as glycolysis, fatty acid oxidation, and glutamine metabolism, support secure vascular migration and proliferation, energy and biomass production, as well as redox homeostasis maintenance during vessel formation. Nevertheless, perturbation of EC metabolism instigates vascular dysregulation-associated diseases, especially cancer. AIM OF REVIEW In this review, we aim to discuss the metabolic regulation of angiogenesis by EC metabolites and metabolic enzymes, as well as prospect the possible therapeutic opportunities and strategies targeting EC metabolism. KEY SCIENTIFIC CONCEPTS OF REVIEW In this work, we discuss various aspects of EC metabolism considering normal and diseased vasculature. Of relevance, we highlight that the implications of EC metabolism-targeted intervention (chiefly by metabolic enzymes or metabolites) could be harnessed in orchestrating a spectrum of pathological angiogenesis-associated diseases.
Collapse
Affiliation(s)
- Yun Liu
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Zifang Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yikun Li
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China; College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Yating Chen
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Xuan Zhao
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
| | - Miaomiao Wu
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, Hunan 410128, China.
| | - Yaoyao Xia
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
| |
Collapse
|
|
5
|
Lee Y, Fang Y, Kuila S, Imoukhuede PI. Cross-family interactions of vascular endothelial growth factors and platelet-derived growth factors on the endothelial cell surface: A computational model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.27.640640. [PMID: 40093087 PMCID: PMC11908192 DOI: 10.1101/2025.02.27.640640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Angiogenesis, the formation of new vessels from existing vessels, is mediated by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Despite discoveries supporting the cross-family interactions between VEGF and PDGF families, sharing the binding partners between them makes it challenging to identify growth factors that predominantly affect angiogenesis. Systems biology offers promises to untangle this complexity. Thus, in this study, we developed a mass-action kinetics-based computational model for cross-family interactions between VEGFs (VEGF-A, VEGF-B, and PlGF) and PDGFs (PDGF-AA, PDGF-AB, and PDGF-BB) with their receptors (VEGFR1, VEGFR2, NRP1, PDGFRα, and PDGFRβ). The model, parametrized with our literature mining and surface resonance plasmon assays, was validated by comparing the concentration of VEGFR1 complexes with a previously constructed angiogenesis model. The model predictions include five outcomes: 1) the percentage of free or bound ligands and 2) receptors, 3) the concentration of free ligands, 4) the percentage of ligands occupying each receptor, and 5) the concentration of ligands that is bound to each receptor. We found that at equimolar ligand concentrations (1 nM), PlGF and VEGF-A were the main binding partners of VEGFR1 and VEGFR2, respectively. Varying the density of receptors resulted in the following five outcomes: 1) Increasing VEGFR1 density depletes the free PlGF concentration, 2) increasing VEGFR2 density decreases PDGF:PDGFRα complexes, 3) increased NRP1 density generates a biphasic concentration of the free PlGF, 4) increased PDGFRα density increases PDGFs:PDGFRα binding, and 5) increasing PDGFRβ density increases VEGF-A:PDGFRβ. Our model offers a reproducible, fundamental framework for exploring cross-family interactions that can be extended to the tissue level or intracellular molecular level. Also, our model may help develop therapeutic strategies in pathological angiogenesis by identifying the dominant complex in the cell signaling. Author summary New blood vessel formation from existing ones is essential for growth, healing, and reproduction. However, when this process is disrupted-either too much or too little-it can contribute to diseases such as cancer and peripheral arterial disease. Two key families of proteins, vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGFs), regulate this process. Traditionally, scientists believed that VEGFs only bind to VEGF receptors and PDGFs to PDGF receptors. However, recent findings show that these proteins can interact with each other's receptors, making it more challenging to understand and control blood vessel formation. To clarify these complex interactions, we combined computer modeling with biological data to map out which proteins bind to which receptors and to what extent. Our findings show that when VEGFs and PDGFs are present in equal amounts, VEGFs are the primary binding partners for VEGF receptors. We also explored how changes in receptor levels affect these interactions in disease-like conditions. This work provides a foundational computational model for studying cross-family interactions, which can be expanded to investigate tissue-level effects and processes inside cells. Ultimately, our model may help develop better treatments for diseases linked to abnormal blood vessel growth by identifying key protein-receptor interactions.
Collapse
|
|
6
|
Folestad E, Mehlem A, Ning FC, Oosterveld T, Palombo I, Singh J, Olauson H, Witasp A, Thorell A, Stenvinkel P, Ebefors K, Nyström J, Eriksson U, Falkevall A. Vascular endothelial growth factor B-mediated fatty acid flux in the adipose-kidney axis contributes to lipotoxicity in diabetic kidney disease. Kidney Int 2025; 107:492-507. [PMID: 39689809 DOI: 10.1016/j.kint.2024.11.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 11/11/2024] [Accepted: 11/18/2024] [Indexed: 12/19/2024]
Abstract
A common observation in diabetic kidney disease is lipid accumulation, but the mechanism(s) underlying this pathology is unknown. Inhibition of Vascular endothelial growth factor B (VEGF-B) signaling was shown to prevent glomerular lipid accumulation and ameliorated diabetic kidney disease in experimental models. Here, we examined kidney biopsies from patients with Type 2 (84%) and Type 1 diabetes (16%), combined with data mining of RNA-seq dataset analyses in patients with diabetic kidney disease. In glomeruli, mesangial cell-derived VEGF-B expression was increased, and glomerular lipid accumulation positively correlated with impaired kidney function. Tubular lipid accumulation also associated with kidney dysfunction but was independent of tubular-derived VEGF-B expression. In vitro, the uptake of the fatty acid analogue, BODIPY-FA, was quantified. VEGF-B treatment increased BODIPY-FA uptake in endothelial cells, whilst pre-incubation with neutralizing antibodies against VEGF-B and its receptor VEGFR1 abolished this uptake. Transcriptome analyses of kidney and white adipose tissue from diabetic macaques showed that VEGF-B expression was higher in white adipose tissue than in kidney, and expression of VEGF-B was increased in white adipose tissue from patients with diabetic kidney disease. Analyses in diabetic transgenic mice demonstrated that expression of VEGF-B in adipocytes determined the lipolytic activity, dyslipidemia, kidney lipid accumulation and the development of diabetic kidney disease. Overall, VEGF-B is a regulator of kidney lipotoxicity in diabetic kidney disease, by controlling white adipose tissue lipolysis as well as endothelial fatty acid transport in glomeruli. Our data propose that assessment of kidney lipid accumulation, and VEGF-B expression can serve as biomarkers for early diabetic kidney disease.
Collapse
Affiliation(s)
- Erika Folestad
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Annika Mehlem
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Frank Chenfei Ning
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Timo Oosterveld
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Isolde Palombo
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Jaskaran Singh
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Hannes Olauson
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna Witasp
- Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Anders Thorell
- Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Surgery and Anaesthesiology, Ersta Hospital, Stockholm, Sweden
| | - Peter Stenvinkel
- Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Kerstin Ebefors
- Lundberg Laboratory for Kidney Research, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jenny Nyström
- Lundberg Laboratory for Kidney Research, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ulf Eriksson
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Annelie Falkevall
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
| |
Collapse
|
|
7
|
Tawfeeq HR, Lackey AI, Zhou Y, Diolintzi A, Zacharisen SM, Lau YH, Quadro L, Storch J. Tissue-Specific Ablation of Liver Fatty Acid-Binding Protein Induces a Metabolically Healthy Obese Phenotype in Female Mice. Nutrients 2025; 17:753. [PMID: 40077623 PMCID: PMC11901660 DOI: 10.3390/nu17050753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/11/2025] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
Background/Objectives: Obesity is associated with numerous metabolic complications including insulin resistance, dyslipidemia, and a reduced capacity for physical activity. Whole-body ablation of liver fatty acid-binding protein (LFABP) in mice was shown to alleviate several of these metabolic complications; high-fat (HF)-fed LFABP knockout (LFABP-/-) mice developed higher fat mass than their wild-type (WT) counterparts but displayed a metabolically healthy obese (MHO) phenotype with normoglycemia, normoinsulinemia, and reduced hepatic steatosis compared with WT. Since LFABP is expressed in both liver and intestine, in the present study, we generated LFABP conditional knockout (cKO) mice to determine the contributions of LFABP specifically within the liver or within the intestine, to the whole-body phenotype of the global knockout. Methods: Female liver-specific LFABP knockout (LFABPliv-/-), intestine-specific LFABP knockout (LFABPint-/-), and "floxed" LFABP (LFABPfl/fl) control mice were fed a 45% Kcal fat semipurified HF diet for 12 weeks. Results: While not as dramatic as found for whole-body LFABP-/- mice, both LFABPliv-/- and LFABPint-/- mice had significantly higher body weights and fat mass compared with LFABPfl/fl control mice. As with the global LFABP nulls, both LFABPliv-/- and LFABPint-/- mice remained normoglycemic and normoinsulinemic. Despite their greater fat mass, the LFABPliv-/- mice did not develop hepatic steatosis. Additionally, LFABPliv-/- and LFABPint-/- mice had higher endurance exercise capacity when compared with LFABPfl/fl control mice. Conclusions: The results suggest, therefore, that either liver-specific or intestine-specific ablation of LFABP in female mice is sufficient to induce, at least in part, the MHO phenotype observed following whole-body ablation of LFABP.
Collapse
Affiliation(s)
- Hiba Radhwan Tawfeeq
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
- Rutgers Center for Lipid Research, New Brunswick, NJ 08901, USA
| | - Atreju I. Lackey
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
- Rutgers Center for Lipid Research, New Brunswick, NJ 08901, USA
| | - Yinxiu Zhou
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
| | - Anastasia Diolintzi
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
- Rutgers Center for Lipid Research, New Brunswick, NJ 08901, USA
| | - Sophia M. Zacharisen
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
| | - Yin Hei Lau
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
| | - Loredana Quadro
- Rutgers Center for Lipid Research, New Brunswick, NJ 08901, USA
- Department of Food Science, Rutgers University, New Brunswick, NJ 07102, USA
| | - Judith Storch
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
- Rutgers Center for Lipid Research, New Brunswick, NJ 08901, USA
| |
Collapse
|
|
8
|
Mo H, Yue P, Li Q, Tan Y, Yan X, Liu X, Xu Y, Luo Y, Palihati S, Yi C, Zhang H, Yuan M, Yang B. The role of liver sinusoidal endothelial cells in metabolic dysfunction-associated steatotic liver diseases and liver cancer: mechanisms and potential therapies. Angiogenesis 2025; 28:14. [PMID: 39899173 DOI: 10.1007/s10456-025-09969-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 01/15/2025] [Indexed: 02/04/2025]
Abstract
Liver sinusoidal endothelial cells (LSECs), with their unique morphology and function, have garnered increasing attention in chronic liver disease research. This review summarizes the critical roles of LSECs under physiological conditions and in two representative chronic liver diseases: metabolic dysfunction-associated steatotic liver disease (MASLD) and liver cancer. Under physiological conditions, LSECs act as selective barriers, regulating substance exchange and hepatic blood flow. Interestingly, LSECs exhibit contrasting roles at different stages of disease progression: in the early stages, they actively resist disease advancement and help restore sinusoidal homeostasis; whereas in later stages, they contribute to disease worsening. During this transition, LSECs undergo capillarization, lose their characteristic markers, and become dysfunctional. As the disease progresses, LSECs closely interact with hepatocytes, hepatic stellate cells, various immune cells, and tumor cells, driving processes such as steatosis, inflammation, fibrosis, angiogenesis, and carcinogenesis. Consequently, targeting LSECs represents a promising therapeutic strategy for chronic liver diseases. Relevant therapeutic targets and potential drugs are summarized in this review.
Collapse
Affiliation(s)
- Hanjun Mo
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Pengfei Yue
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Qiaoqi Li
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yinxi Tan
- Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing, China
| | - Xinran Yan
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyue Liu
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yuanwei Xu
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yingzhe Luo
- Department of Medical Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, No. 39 Shierqiao Road, Chengdu, 610075, Sichuan, China
| | - Suruiya Palihati
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Cheng Yi
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Hua Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, China.
- Key Laboratory of Chronobiology (Sichuan University), National Health Commission of China, Chengdu, 610041, China.
| | - Minlan Yuan
- Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China.
| | - Biao Yang
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
| |
Collapse
|
|
9
|
Pérez-Revuelta L, Pérez-Boyero D, Pérez-Martín E, Cabedo VL, Téllez de Meneses PG, Weruaga E, Díaz D, Alonso JR. Neuroprotective Effects of VEGF-B in a Murine Model of Aggressive Neuronal Loss with Childhood Onset. Int J Mol Sci 2025; 26:538. [PMID: 39859255 PMCID: PMC11765331 DOI: 10.3390/ijms26020538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
In recent decades, the scientific community has faced a major challenge in the search for new therapies that can slow down or alleviate the process of neuronal death that accompanies neurodegenerative diseases. This study aimed to identify an effective therapy using neurotrophic factors to delay the rapid and aggressive cerebellar degeneration experienced by the Purkinje Cell Degeneration (PCD) mouse, a model of childhood-onset neurodegeneration with cerebellar atrophy (CONDCA). Initially, we analyzed the changes in the expression of several neurotrophic factors related to the degenerative process itself, identifying changes in insulin-like growth factor 1 (IGF-1) and Vascular Endothelial Growth Factor B (VEGF-B) in the affected animals. Then, we administered pharmacological treatments using human recombinant IGF-1 (rhIGF-1) or VEGF-B (rhVEGF-B) proteins, considering their temporal variations during the degenerative process. The effects of these treatments on motor, cognitive, and social behavior, as well as on cerebellar destructuration were analyzed. Whereas treatment with rhIGF-1 did not demonstrate any neuroprotective effect, rhVEGF-B administration at moderate dosages stopped the process of neuronal death and restored motor, cognitive, and social functions altered in PCD mice (and CONDCA patients). However, increasing the frequency of rhVEGF-B administration had a detrimental effect on Purkinje cell survival, suggesting an inverted U-shaped dose-response curve of this substance. Additionally, we demonstrate that this neuroprotective effect was achieved through a partial inhibition or delay of apoptosis. These findings provide strong evidence supporting the use of rhVEGF-B as a pharmacological agent to limit severe cerebellar neurodegenerative processes.
Collapse
Affiliation(s)
- Laura Pérez-Revuelta
- Laboratory of Neuronal Plasticity and Neurorepair, Institute of Neuroscience of Castile and Leon (INCyL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.P.-R.)
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - David Pérez-Boyero
- Laboratory of Neuronal Plasticity and Neurorepair, Institute of Neuroscience of Castile and Leon (INCyL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.P.-R.)
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Ester Pérez-Martín
- Neuroscience Innovative Technologies, Neurostech, 33428 Llanera, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Intervenciones Traslacionales para la Salud, 33011 Oviedo, Spain
| | - Valeria Lorena Cabedo
- Laboratory of Neuronal Plasticity and Neurorepair, Institute of Neuroscience of Castile and Leon (INCyL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.P.-R.)
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Pablo González Téllez de Meneses
- Laboratory of Neuronal Plasticity and Neurorepair, Institute of Neuroscience of Castile and Leon (INCyL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.P.-R.)
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Eduardo Weruaga
- Laboratory of Neuronal Plasticity and Neurorepair, Institute of Neuroscience of Castile and Leon (INCyL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.P.-R.)
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - David Díaz
- Laboratory of Neuronal Plasticity and Neurorepair, Institute of Neuroscience of Castile and Leon (INCyL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.P.-R.)
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - José Ramón Alonso
- Laboratory of Neuronal Plasticity and Neurorepair, Institute of Neuroscience of Castile and Leon (INCyL), Universidad de Salamanca, 37007 Salamanca, Spain; (L.P.-R.)
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| |
Collapse
|
|
10
|
Tawfeeq HR, Lackey AI, Zhou Y, Diolointzi A, Zacharisen S, Lau YH, Quadro L, Storch J. Tissue-Specific Ablation of Liver Fatty Acid-Binding Protein Induces a Metabolically Healthy Obese Phenotype in Female Mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.02.631082. [PMID: 39803463 PMCID: PMC11722216 DOI: 10.1101/2025.01.02.631082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
Background/Objectives Obesity is associated with numerous metabolic complications including insulin resistance, dyslipidemia, and a reduced capacity for physical activity. Whole-body ablation of liver fatty acid-binding protein (LFABP) in mice was shown to alleviate several of these metabolic complications; high fat (HF) fed LFABP knockout (LFABP-/-) mice developed higher fat mass than their wild-type (WT) counterparts but displayed a metabolically healthy obese (MHO) phenotype with normoglycemia, normoinsulinemia, and reduced hepatic steatosis compared with WT. LFABP is expressed in both liver and intestine, thus in the present study, LFABP conditional knockout (cKO) mice were generated to determine the contributions of LFABP specifically within the liver or the intestine to the whole body phenotype of the global knockout. Methods Female liver-specific LFABP knockout (LFABPliv-/-), intestine-specific LFABP knockout (LFABPint-/-), and floxed LFABP (LFABPfl/fl) control mice were fed a 45% Kcal fat semipurified HF diet for 12 weeks. Results While not as dramatic as found for whole-body LFABP-/- mice, both LFABPliv-/- and LFABPint-/- mice had significantly higher body weights and fat mass compared with LFABPfl/fl control mice. As with the global LFABP nulls, both LFABPliv-/- and LFABPint-/- mice remained normoglycemic and normoinsulinemic. Despite their greater fat mass, the LFABPliv-/- mice did not develop hepatic steatosis. Additionally, LFABPliv-/- and LFABPint-/- mice had higher endurance exercise capacity when compared with LFABPfl/fl control mice. Conclusions The results suggest, therefore, that either liver-specific or intestine-specific ablation of LFABP in female mice is sufficient to induce, at least in part, the MHO phenotype observed following whole-body ablation of LFABP.
Collapse
Affiliation(s)
- Hiba Radhwan Tawfeeq
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
- Rutgers Center for Lipid Research, New Brunswick, New Jersey
| | - Atreju I Lackey
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
- Rutgers Center for Lipid Research, New Brunswick, New Jersey
| | - Yinxiu Zhou
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
| | - Anastasia Diolointzi
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
- Rutgers Center for Lipid Research, New Brunswick, New Jersey
| | - Sophia Zacharisen
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
| | - Yin Hei Lau
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
| | - Loredana Quadro
- Rutgers Center for Lipid Research, New Brunswick, New Jersey
- Department of Food Science, Rutgers University, New Brunswick, New Jersey
| | - Judith Storch
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
- Rutgers Center for Lipid Research, New Brunswick, New Jersey
| |
Collapse
|
|
11
|
Wang L, Jin J, Zhang N, Dai Y, Bai X, Li J, Yu Y, Shi X, Bai H, Yang Q, Jiang B, Ben J, Zhang H, Li X, Chen Q, Zhu X. VEGFB promotes adipose tissue thermogenesis by inhibiting norepinephrine clearance in macrophages. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167536. [PMID: 39378967 DOI: 10.1016/j.bbadis.2024.167536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 10/10/2024]
Abstract
Adipokines play key roles in adaptive thermogenesis of beige adipocytes, though its detailed regulatory mechanisms are not fully understood. In the present study, we identify a critical function of vascular endothelial growth factor B (VEGFB)/vascular endothelial growth factor receptor 1 (VEGFR1) signaling in improving thermogenesis in white adipose tissue (WAT). In mouse subcutaneous WAT (scWAT), thermogenesis activation leads to the up-regulation of VEGFB in adipocytes and its receptor VEGFR1 in macrophages. Ablation of adipocyte VEGFB results in deficiency in murine WAT browning. Meanwhile, supplementation of VEGFB promotes WAT thermogenesis, but this effect is blocked by knockout of macrophage VEGFR1. Mechanistic studies show that the VEGFB-activated VEGFR1 inhibits p38 MAPK signaling through its dissociation with receptor for activated C kinase 1, thereby preventing norepinephrine transporter (solute carrier family 6 member 2) and norepinephrine-degrative monoamine oxidase a mediated norepinephrine clearance in macrophages. Our findings demonstrate that VEGFB/VEGFR1 circuit contributes to the WAT thermogenesis.
Collapse
Affiliation(s)
- Lei Wang
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China; Department of Pathology, Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Jing Jin
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Nuo Zhang
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Yan Dai
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Xueya Bai
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Jinhao Li
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Yueqi Yu
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Xiaoling Shi
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Hui Bai
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Qing Yang
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Bin Jiang
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Jingjing Ben
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Hanwen Zhang
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Xiaoyu Li
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Qi Chen
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China; The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China.
| | - Xudong Zhu
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Molecular Intervention, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
| |
Collapse
|
|
12
|
Kane K, Edwards D, Chen J. The influence of endothelial metabolic reprogramming on the tumor microenvironment. Oncogene 2025; 44:51-63. [PMID: 39567756 PMCID: PMC11706781 DOI: 10.1038/s41388-024-03228-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/22/2024]
Abstract
Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial cells are relatively quiescent with organ-specific expression signatures and metabolic profiles. In cancer, ECs are metabolically reprogrammed to promote the formation of new blood vessels to fuel tumor growth and metastasis. In addition to EC's role on tumor cells, the tortuous tumor vasculature contributes to an immunosuppressive environment by limiting T lymphocyte infiltration and activity while also promoting the recruitment of other accessory pro-angiogenic immune cells. These elements aid in the metastatic spreading of cancer cells and contribute to therapeutic resistance. The concept of restoring a more stabilized vasculature in concert with cancer immunotherapy is emerging as a potential approach to overcoming barriers in cancer treatment. This review summarizes the metabolism of endothelial cells, their regulation of nutrient uptake and delivery, and their impact in shaping the tumor microenvironment and anti-tumor immunity. We highlight new therapeutic approaches that target the tumor vasculature and harness the immune response. Appreciating the integration of metabolic state and nutrient levels and the crosstalk among immune cells, tumor cells, and ECs in the TME may provide new avenues for therapeutic intervention.
Collapse
Affiliation(s)
- Kelby Kane
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
| | - Deanna Edwards
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
- Division of Rheumatology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jin Chen
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.
- Division of Rheumatology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.
| |
Collapse
|
|
13
|
Citrin KM, Chaube B, Fernández-Hernando C, Suárez Y. Intracellular endothelial cell metabolism in vascular function and dysfunction. Trends Endocrinol Metab 2024:S1043-2760(24)00296-0. [PMID: 39672762 DOI: 10.1016/j.tem.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/04/2024] [Accepted: 11/11/2024] [Indexed: 12/15/2024]
Abstract
Endothelial cells (ECs) form the inner lining of blood vessels that is crucial for vascular function and homeostasis. They regulate vascular tone, oxidative stress, and permeability. Dysfunction leads to increased permeability, leukocyte adhesion, and thrombosis. ECs undergo metabolic changes in conditions such as wound healing, cancer, atherosclerosis, and diabetes, and can influence disease progression. We discuss recent research that has revealed diverse intracellular metabolic pathways in ECs that are tailored to their functional needs, including lipid handling, glycolysis, and fatty acid oxidation (FAO). Understanding EC metabolic signatures in health and disease will be crucial not only for basic biology but can also be exploited when designing new therapies to target EC-related functions in different vascular diseases.
Collapse
Affiliation(s)
- Kathryn M Citrin
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA
| | - Balkrishna Chaube
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA; Indian Institute of Technology Dharwad, Karnataka, India
| | - Carlos Fernández-Hernando
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Yajaira Suárez
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
| |
Collapse
|
|
14
|
Liu J, Quan L, Wang J, Zhang G, Cai L, Pan Z, Liu S, Zhu C, Wu R, Wang L, Shu G, Jiang Q, Wang S. Knockdown of VEGF-B improves HFD-induced insulin resistance by enhancing glucose uptake in vascular endothelial cells via the PI3K/Akt pathway. Int J Biol Macromol 2024; 285:138279. [PMID: 39631591 DOI: 10.1016/j.ijbiomac.2024.138279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/18/2024] [Accepted: 11/30/2024] [Indexed: 12/07/2024]
Abstract
Vascular endothelial growth factor B (VEGF-B) has been suggested to play a crucial role in regulating whole-body glucose homeostasis. However, the involved mechanisms are not fully understood. This study aimed to elucidate the regulatory effects and mechanisms of VEGF-B on glucose uptake in skeletal muscle, focusing on glucose uptake by skeletal muscle cells and vascular endothelial cells. Our results showed that a high-fat diet (HFD) induced significant increase in VEGF-B expression and decrease in glucose uptake by skeletal muscle, accompanied by elevated serum glucose levels. Interestingly, VEGF-B had no direct effect on glucose uptake by skeletal muscle cells (differentiated C2C12). Instead, VEGF-B inhibited glucose uptake of vascular endothelial cells bEnd.3 and subsequent trans-endothelial glucose transport, ultimately resulting in decreased glucose uptake by skeletal muscle cells. Furthermore, VEGF-B suppressed glucose uptake of vascular endothelial cells by downregulating the expression of glucose transporter 1 (GLUT1) through the VEGFR-PI3K/Akt signaling pathway. In vivo, knockdown of VEGF-B in skeletal muscle increased the HFD-impaired glucose uptake of skeletal muscle and improved the HFD-induced glucose intolerance and insulin resistance. This beneficial effect of VEGF-B knockdown was associated with the elevated expression of GLUT1 in the plasma membrane and the activation of the PI3K/Akt pathway in skeletal muscle. In conclusion, our findings demonstrated that knockdown of VEGF-B improved HFD-induced insulin resistance by enhancing glucose uptake in vascular endothelial cells via the PI3K/Akt pathway. These results highlighted the critical role of VEGF-B in regulating glucose uptake by vascular endothelial cells in skeletal muscle, providing a potential new target for improving obesity-induced glucose homeostasis imbalance.
Collapse
Affiliation(s)
- Jinhao Liu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Lulu Quan
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Junfeng Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Gonghao Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Lilin Cai
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Zhe Pan
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Shilong Liu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Canjun Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Ruifan Wu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Lina Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Gang Shu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Songbo Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry and State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; Yunfu Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Wens Foodstuff Group Co., Ltd., Yunfu 527400, China.
| |
Collapse
|
|
15
|
Pang B, Dong G, Pang T, Sun X, Liu X, Nie Y, Chang X. Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction. Angiogenesis 2024; 27:623-639. [PMID: 39060773 PMCID: PMC11564294 DOI: 10.1007/s10456-024-09938-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024]
Abstract
As a vital component of blood vessels, endothelial cells play a key role in maintaining overall physiological function by residing between circulating blood and semi-solid tissue. Various stress stimuli can induce endothelial injury, leading to the onset of corresponding diseases in the body. In recent years, the importance of mitochondria in vascular endothelial injury has become increasingly apparent. Mitochondria, as the primary site of cellular aerobic respiration and the organelle for "energy information transfer," can detect endothelial cell damage by integrating and receiving various external stress signals. The generation of reactive oxygen species (ROS) and mitochondrial dysfunction often determine the evolution of endothelial cell injury towards necrosis or apoptosis. Therefore, mitochondria are closely associated with endothelial cell function, helping to determine the progression of clinical diseases. This article comprehensively reviews the interconnection and pathogenesis of mitochondrial-induced vascular endothelial cell injury in cardiovascular diseases, renal diseases, pulmonary-related diseases, cerebrovascular diseases, and microvascular diseases associated with diabetes. Corresponding therapeutic approaches are also provided. Additionally, strategies for using clinical drugs to treat vascular endothelial injury-based diseases are discussed, aiming to offer new insights and treatment options for the clinical diagnosis of related vascular injuries.
Collapse
Affiliation(s)
- Boxian Pang
- Beijing University of Chinese Medicine, Beijing, China
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | | | - Tieliang Pang
- Beijing Anding hospital, Capital Medical University, Beijing, China
| | - Xinyao Sun
- Beijing University of Chinese Medicine, Beijing, China
| | - Xin Liu
- Bioscience Department, University of Nottingham, Nottingham, UK
| | - Yifeng Nie
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China.
| | - Xing Chang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, 5 Beixiagge, Xicheng District, Beijing, China.
| |
Collapse
|
|
16
|
Tosato G, Wang Y. Celebrating the 1945 JNCI pioneering contribution to antiangiogenic therapy for cancer. J Natl Cancer Inst 2024; 116:1715-1720. [PMID: 39178374 DOI: 10.1093/jnci/djae181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 07/25/2024] [Accepted: 07/29/2024] [Indexed: 08/25/2024] Open
Affiliation(s)
- Giovanna Tosato
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yuyi Wang
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
17
|
Xiao W, Lee LY, Loscalzo J. Metabolic Responses to Redox Stress in Vascular Cells. Antioxid Redox Signal 2024; 41:793-817. [PMID: 38985660 PMCID: PMC11876825 DOI: 10.1089/ars.2023.0476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 11/11/2023] [Indexed: 07/12/2024]
Abstract
Significance: Redox stress underlies numerous vascular disease mechanisms. Metabolic adaptability is essential for vascular cells to preserve energy and redox homeostasis. Recent Advances: Single-cell technologies and multiomic studies demonstrate significant metabolic heterogeneity among vascular cells in health and disease. Increasing evidence shows that reductive or oxidative stress can induce metabolic reprogramming of vascular cells. A recent example is intracellular L-2-hydroxyglutarate accumulation in response to hypoxic reductive stress, which attenuates the glucose flux through glycolysis and mitochondrial respiration in pulmonary vascular cells and provides protection against further reductive stress. Critical Issues: Regulation of cellular redox homeostasis is highly compartmentalized and complex. Vascular cells rely on multiple metabolic pathways, but the precise connectivity among these pathways and their regulatory mechanisms is only partially defined. There is also a critical need to understand better the cross-regulatory mechanisms between the redox system and metabolic pathways as perturbations in either systems or their cross talk can be detrimental. Future Directions: Future studies are needed to define further how multiple metabolic pathways are wired in vascular cells individually and as a network of closely intertwined processes given that a perturbation in one metabolic compartment often affects others. There also needs to be a comprehensive understanding of how different types of redox perturbations are sensed by and regulate different cellular metabolic pathways with specific attention to subcellular compartmentalization. Lastly, integration of dynamic changes occurring in multiple metabolic pathways and their cross talk with the redox system is an important goal in this multiomics era. Antioxid. Redox Signal. 41,793-817.
Collapse
Affiliation(s)
- Wusheng Xiao
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Toxicology, School of Public Health, Peking University, Beijing, China
| | - Laurel Y. Lee
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Joseph Loscalzo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
18
|
Cooper M, Cherney DZ, Greene TH, Heerspink HJ, Jardine M, Lewis JB, Wong MG, Baquero E, Heise M, Jochems J, Lanchoney D, Liss C, Reiser D, Scotney P, Velkoska E, Dwyer JP. Vascular Endothelial Growth Factor-B Blockade with CSL346 in Diabetic Kidney Disease: A Phase 2A Randomized Controlled Trial. J Am Soc Nephrol 2024; 35:1546-1557. [PMID: 39150859 PMCID: PMC11543004 DOI: 10.1681/asn.0000000000000438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 08/06/2024] [Indexed: 08/18/2024] Open
Abstract
Key Points The vascular endothelial growth factor B inhibitor CSL346 (8 or 16 mg/kg q4w) did not reduce urinary albumin-creatinine ratio at week 16 versus placebo in patients with type 2 diabetes mellitus and diabetic kidney disease. CSL346 was generally well tolerated at both doses; however, CSL346 (16 mg/kg) significantly increased diastolic BP versus placebo. Background Increased vascular endothelial growth factor B (VEGF-B) expression in patients with diabetic kidney disease (DKD) is associated with increased lipid deposition in glomerular podocytes. Reducing VEGF-B activity in animal models of DKD using an anti–VEGF-B antibody improved histological evidence of glomerular injury and reduced albuminuria, effects attributed to prevention of ectopic lipid deposition in the kidney. CSL346 is a novel humanized monoclonal antibody that binds VEGF-B with high affinity. Targeting VEGF-B in patients with type 2 diabetes mellitus may improve DKD progression markers. Methods An international, randomized, double-blind, placebo-controlled, phase 2a study (NCT04419467 ) assessed CSL346 (8 or 16 mg/kg subcutaneously every 4 weeks for 12 weeks) in participants with type 2 diabetes mellitus and a urinary albumin-creatinine ratio (UACR) ≥150 mg/g (17.0 mg/mmol), and eGFR >20 ml/min per 1.73 m2. Efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of CSL346 were evaluated. The primary analysis compared the change from baseline in log-transformed UACR between the two CSL346 dose groups combined versus placebo at week 16. Results In total, 114 participants were randomized. CSL346 did not significantly reduce UACR compared with placebo at week 16 (combined CSL346 group difference from placebo [95% confidence interval], 4.0% [−14.7 to 26.8]). Furthermore, no effect was seen in participant subgroups (degree of kidney impairment or sodium-glucose cotransporter 2 inhibitor use) or on urinary biomarkers reflecting proximal tubular injury. CSL346 was generally well tolerated; however, diastolic BP was significantly higher with CSL346 16 mg/kg versus placebo from week 2 onward, with differences ranging from +3.8 to +5.3 mm Hg (P = 0.002 at week 16). Conclusions CSL346 did not reduce UACR compared with placebo at 16 weeks in participants with type 2 diabetes mellitus and DKD and was associated with an increase in diastolic BP. Clinical Trial registry name and registration number: VEGF-B Blockade with the Monoclonal Antibody CSL346 in Subjects with DKD, NCT04419467 .
Collapse
Affiliation(s)
| | | | - Tom H. Greene
- Division of Biostatistics, University of Utah, Salt Lake City, Utah
| | - Hiddo J.L. Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- The George Institute for Global Health, Sydney, New South Wales, Australia
| | - Meg Jardine
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
- Concord Repatriation General Hospital, Sydney, New South Wales, Australia
| | - Julia B. Lewis
- Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Muh Geot Wong
- Department of Renal Medicine, Concord Repatriation General Hospital, Sydney, New South Wales, Australia
| | | | - Mark Heise
- CSL Behring LLC, King of Prussia, Pennsylvania
| | | | | | | | | | - Pierre Scotney
- CSL Ltd., Bio21 Institute, Melbourne, Victoria, Australia
| | - Elena Velkoska
- CSL Ltd., Bio21 Institute, Melbourne, Victoria, Australia
| | - Jamie P. Dwyer
- Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah
| |
Collapse
|
|
19
|
Nilsson I, Su EJ, Fredriksson L, Sahlgren BH, Bagoly Z, Moessinger C, Stefanitsch C, Ning FC, Zeitelhofer M, Muhl L, Lawrence ALE, Scotney PD, Lu L, Samén E, Ho H, Keep RF, Medcalf RL, Lawrence DA, Eriksson U. Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.11.617532. [PMID: 39416206 PMCID: PMC11483068 DOI: 10.1101/2024.10.11.617532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Cerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management.
Collapse
Affiliation(s)
- Ingrid Nilsson
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
- These authors contributed equally
- Lead contact: (I.N.)
| | - Enming J. Su
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- These authors contributed equally
| | - Linda Fredriksson
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Benjamin Heller Sahlgren
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Zsuzsa Bagoly
- MTA-DE Lendület “Momentum” Hemostasis and Stroke Research Group, Department of Laboratory Medicine, Division of Clinical Laboratory Sciences, Faculty of Medicine, University of Debrecen, Hungary
| | - Christine Moessinger
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Christina Stefanitsch
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Frank Chenfei Ning
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Manuel Zeitelhofer
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Lars Muhl
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Anna-Lisa E. Lawrence
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | | | - Li Lu
- Karolinska Experimental Research and Imaging Centre, Karolinska University Hospital, Stockholm, Sweden
| | - Erik Samén
- Department of Nuclear Medicine and Medical Physics, Karolinska University Hospital, Stockholm, Sweden
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Heidi Ho
- Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Victoria, Australia
| | - Richard F. Keep
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA
| | - Robert L. Medcalf
- Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Victoria, Australia
| | - Daniel A. Lawrence
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ulf Eriksson
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
20
|
Li R, Zhou N, Zhang C, Wu M, Xu W, Cheng J, Tao L, Li Z, Zhang Y. Cardiotoxicity risk induced by sanitary insecticide Dimefluthrin. CHEMOSPHERE 2024; 364:142910. [PMID: 39067820 DOI: 10.1016/j.chemosphere.2024.142910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/13/2024] [Accepted: 07/18/2024] [Indexed: 07/30/2024]
Abstract
Dimefluthrin (DIM) is a commonly utilized sanitary insecticide, predominantly employed for indoor pest management within residential and public environments directly interacting with human habitation. However, the usage of DIM is escalating with increasing mosquito resistance, prompting concerns about its health risks. Here, using zebrafish as a research model, we systematically evaluated DIM's impact on human health. Findings revealed significant health hazards during embryonic development, including reduced hatching rates, shortened body lengths, and organ malformations, notably affecting the heart. It was explored the mechanism of DIM-induced cardiotoxicity in zebrafish, and histopathological analyses revealed that DIM resulted in ventricular linearization in zebrafish embryos. Antioxidant enzyme activities were reduced and cardiac reactive oxygen species (ROS) accumulated after DIM exposure, suggesting clear signs of oxidative stress. Additionally, acridine orange (AO) staining and caspase-3 immunofluorescence demonstrated cardiac apoptosis in Tg (kdrl: EGFP) zebrafish. qPCR analysis implied that DIM induced apoptosis via the p53/Caspase pathway by up-regulating the expression levels of p53, cytochrome C (cyto-C), caspase-9, and caspase-3. Together, our work provided a systematic perspective on the cardiotoxicity of sanitary pesticides, which could offer opportunities for future risk management.
Collapse
Affiliation(s)
- Ruirui Li
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Ning Zhou
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Cheng Zhang
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, 75390, United States
| | - Mengqi Wu
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Wenping Xu
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Jiagao Cheng
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Liming Tao
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Zhong Li
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Yang Zhang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
| |
Collapse
|
|
21
|
Zhang Q, Xia Y, Wang L, Wang Y, Bao Y, Zhao GS. Targeted anti-angiogenesis therapy for advanced osteosarcoma. Front Oncol 2024; 14:1413213. [PMID: 39252946 PMCID: PMC11381227 DOI: 10.3389/fonc.2024.1413213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 08/08/2024] [Indexed: 09/11/2024] Open
Abstract
To date, despite extensive research, the prognosis of advanced osteosarcoma has not improved significantly. Thus, patients experience a reduced survival rate, suggesting that a reevaluation of current treatment strategies is required. Recently, in addition to routine surgery, chemotherapy and radiotherapy, researchers have explored more effective and safer treatments, including targeted therapy, immunotherapy, anti-angiogenesis therapy, metabolic targets therapy, and nanomedicine therapy. The tumorigenesis and development of osteosarcoma is closely related to angiogenesis. Thus, anti-angiogenesis therapy is crucial to treat osteosarcoma; however, recent clinical trials found that it has insufficient efficacy. To solve this problem, the causes of treatment failure and improve treatment strategies should be investigated. This review focuses on summarizing the pathophysiological mechanisms of angiogenesis in osteosarcoma and recent advances in anti-angiogenesis treatment of osteosarcoma. We also discuss some clinical studies, with the aim of providing new ideas to improve treatment strategies for osteosarcoma and the prognosis of patients.
Collapse
Affiliation(s)
- Qiao Zhang
- Department of Pain and Rehabilitation, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yuxuan Xia
- Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - LiYuan Wang
- Department of Spine Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yang Wang
- Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yixi Bao
- Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guo-Sheng Zhao
- Department of Spine Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
22
|
He J, Chen Y, Ding H, Zhou JA, Xing Z, Yang X, Fan Q, Zuo Y, Wang T, Cheng J. Autocrine VEGF-B signaling maintains lipid synthesis and mitochondrial fitness to support T cell immune responses. J Clin Invest 2024; 134:e176586. [PMID: 39145452 PMCID: PMC11324299 DOI: 10.1172/jci176586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 06/20/2024] [Indexed: 08/16/2024] Open
Abstract
T cells rewire their metabolic activities to meet the demand of immune responses, but how to coordinate the immune response by metabolic regulators in activated T cells is unknown. Here, we identified autocrine VEGF-B as a metabolic regulator to control lipid synthesis and maintain the integrity of the mitochondrial inner membrane for the survival of activated T cells. Disruption of autocrine VEGF-B signaling in T cells reduced cardiolipin mass, resulting in mitochondrial damage, with increased apoptosis and reduced memory development. The addition of cardiolipin or modulating VEGF-B signaling improved T cell mitochondrial fitness and survival. Autocrine VEGF-B signaling through GA-binding protein α (GABPα) induced sentrin/SUMO-specific protease 2 (SENP2) expression, which further de-SUMOylated PPARγ and enhanced phospholipid synthesis, leading to a cardiolipin increase in activated T cells. These data suggest that autocrine VEGF-B mediates a signal to coordinate lipid synthesis and mitochondrial fitness with T cell activation for survival and immune response. Moreover, autocrine VEGF-B signaling in T cells provides a therapeutic target against infection and tumors as well as an avenue for the treatment of autoimmune diseases.
Collapse
Affiliation(s)
- Jianli He
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology
| | - Yalan Chen
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology
| | - Huihua Ding
- Department of Rheumatology, Renji Hospital
- Shanghai Institute of Rheumatology, Renji Hospital, and
| | - Jin-An Zhou
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhengcao Xing
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology
| | - Xinyu Yang
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology
| | - Qiuju Fan
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology
| | - Yong Zuo
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology
| | - Tianshi Wang
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology
| | - Jinke Cheng
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology
- Hainan Medical University, Hainan Academy of Medical Sciences, Haikou, Hainan, China
| |
Collapse
|
|
23
|
Mann CG, MacArthur MR, Zhang J, Gong S, AbuSalim JE, Hunter CJ, Lu W, Agius T, Longchamp A, Allagnat F, Rabinowitz J, Mitchell JR, De Bock K, Mitchell SJ. Sulfur Amino Acid Restriction Enhances Exercise Capacity in Mice by Boosting Fat Oxidation in Muscle. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.27.601041. [PMID: 39005372 PMCID: PMC11244859 DOI: 10.1101/2024.06.27.601041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Dietary restriction of the sulfur-containing amino acids methionine and cysteine (SAAR) improves body composition, enhances insulin sensitivity, and extends lifespan; benefits seen also with endurance exercise. Yet, the impact of SAAR on skeletal muscle remains largely unexplored. Here we demonstrate that one week of SAAR in sedentary, young, male mice increases endurance exercise capacity. Indirect calorimetry showed that SAAR increased lipid oxidation at rest and delayed the onset of carbohydrate utilization during exercise. Transcriptomic analysis revealed increased expression of genes involved in fatty acid catabolism especially in glycolytic muscle following SAAR. These findings were functionally supported by increased fatty acid circulatory turnover flux and muscle β-oxidation. Reducing lipid uptake from circulation through endothelial cell (EC)-specific CD36 deletion attenuated the running phenotype. Mechanistically, VEGF-signaling inhibition prevented exercise increases following SAAR, without affecting angiogenesis, implicating noncanonical VEGF signaling and EC CD36-dependent fatty acid transport in regulating exercise capacity by influencing muscle substrate availability.
Collapse
Affiliation(s)
- Charlotte G Mann
- Department of Health Sciences and Technology, ETH Zurich, Zurich 8092, Switzerland
| | - Michael R MacArthur
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
- Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA
| | - Jing Zhang
- Department of Health Sciences and Technology, ETH Zurich, Zurich 8092, Switzerland
| | - Songlin Gong
- Department of Health Sciences and Technology, ETH Zurich, Zurich 8092, Switzerland
| | - Jenna E AbuSalim
- Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Craig J. Hunter
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
- Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA
| | - Wenyun Lu
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
- Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
| | - Thomas Agius
- Department of Vascular Surgery, Lausanne University Hospital (CHUV), Lausanne 1005, Switzerland
| | - Alban Longchamp
- Department of Vascular Surgery, Lausanne University Hospital (CHUV), Lausanne 1005, Switzerland
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Florent Allagnat
- Department of Vascular Surgery, Lausanne University Hospital (CHUV), Lausanne 1005, Switzerland
| | - Joshua Rabinowitz
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
- Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - James R Mitchell
- Department of Health Sciences and Technology, ETH Zurich, Zurich 8092, Switzerland
- Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Katrien De Bock
- Department of Health Sciences and Technology, ETH Zurich, Zurich 8092, Switzerland
| | - Sarah J Mitchell
- Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA
| |
Collapse
|
|
24
|
Chen X, Xu Y, Ju Y, Gu P. Metabolic Regulation of Endothelial Cells: A New Era for Treating Wet Age-Related Macular Degeneration. Int J Mol Sci 2024; 25:5926. [PMID: 38892113 PMCID: PMC11172501 DOI: 10.3390/ijms25115926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/27/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Wet age-related macular degeneration (wet AMD) is a primary contributor to visual impairment and severe vision loss globally, but the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells (ECs) is mainly dictated by angiogenic growth factors. Even though treatments targeting vascular endothelial growth factor (VEGF), like ranibizumab, are widely administered, more than half of patients still exhibit inadequate or null responses, suggesting the involvement of other pathogenic mechanisms. With advances in research in recent years, it has become well recognized that EC metabolic regulation plays an active rather than merely passive responsive role in angiogenesis. Disturbances of these metabolic pathways may lead to excessive neovascularization in angiogenic diseases such as wet AMD, therefore targeted modulation of EC metabolism represents a promising therapeutic strategy for wet AMD. In this review, we comprehensively discuss the potential applications of EC metabolic regulation in wet AMD treatment from multiple perspectives, including the involvement of ECs in wet AMD pathogenesis, the major endothelial metabolic pathways, and novel therapeutic approaches targeting metabolism for wet AMD.
Collapse
Affiliation(s)
- Xirui Chen
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (X.C.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Yang Xu
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (X.C.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Yahan Ju
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (X.C.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Ping Gu
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (X.C.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| |
Collapse
|
|
25
|
Janes PW, Parslow AC, Cao D, Rigopoulos A, Lee FT, Gong SJ, Cartwright GA, Burvenich IJG, Eriksson U, Johns TG, Scott FE, Scott AM. An Anti-VEGF-B Antibody Reduces Abnormal Tumor Vasculature and Enhances the Effects of Chemotherapy. Cancers (Basel) 2024; 16:1902. [PMID: 38791979 PMCID: PMC11119922 DOI: 10.3390/cancers16101902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/06/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key regulators of blood vessel formation, including in tumors, where their deregulated function can promote the production of aberrant, leaky blood vessels, supporting tumor development. Here we investigated the VEGFR1 ligand VEGF-B, which we demonstrate to be expressed in tumor cells and in tumor stroma and vasculature across a range of tumor types. We examined the anti-VEGF-B-specific monoclonal antibody 2H10 in preclinical xenograft models of breast and colorectal cancer, in comparison with the anti-VEGF-A antibody bevacizumab. Similar to bevacizumab, 2H10 therapy was associated with changes in tumor blood vessels and intra-tumoral diffusion consistent with normalization of the tumor vasculature. Accordingly, treatment resulted in partial inhibition of tumor growth, and significantly improved the response to chemotherapy. Our studies indicate the importance of VEGF-B in tumor growth, and the potential of specific anti-VEGF-B treatment to inhibit tumor development, alone or in combination with established chemotherapies.
Collapse
Affiliation(s)
- Peter W. Janes
- Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC 3083, Australia
| | - Adam C. Parslow
- Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia
| | - Diana Cao
- Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia
| | - Angela Rigopoulos
- Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia
| | - Fook-Thean Lee
- Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia
| | - Sylvia J. Gong
- School of Computing, Engineering and Mathematical Sciences, La Trobe University, Melbourne, VIC 3083, Australia
- Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC 3084, Australia
| | - Glenn A. Cartwright
- Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia
| | - Ingrid J. G. Burvenich
- Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC 3083, Australia
| | - Ulf Eriksson
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Solna, Sweden
| | - Terrance G. Johns
- Oncogenic Signalling Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Nedlands, WA 6009, Australia
- Medical School, University of Western Australia, Crawley, WA 6009, Australia
| | - Fiona E. Scott
- Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia
| | - Andrew M. Scott
- Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC 3083, Australia
- Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC 3084, Australia
- Department of Medicine, University of Melbourne, Parkville, VIC 3052, Australia
| |
Collapse
|
|
26
|
Su N, Zheng J, Zhang G, Guan J, Gao X, Cheng Z, Xu C, Xie D, Li Y. Molecular characterization of vascular endothelial growth factor b from spotted sea bass (Lateolabrax maculatus) and its potential roles in decreasing lipid deposition. Int J Biol Macromol 2024; 267:131507. [PMID: 38604419 DOI: 10.1016/j.ijbiomac.2024.131507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/15/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
Vascular endothelial growth factor B (VEGFB), a member of the VEGF family, exhibits limited angiogenic activity in mammals but plays an unexpected role in targeting lipids to peripheral tissues. However, its role in lipid metabolism in fish is unknown. In this study, the vegfb gene was cloned and characterized from spotted sea bass (Lateolabrax maculatus). It encodes 254 amino acids and possesses the typical characteristics of the Vegfb family, demonstrating high homology with those from other vertebrate species. The vegfb gene exhibits the highest expression levels in the liver, followed by the gills, intestine, and adipose tissues in spotted sea bass. In vivo, high-lipid diets decreased vegfb expression and increased lipid deposition in liver of fish. In vitro, palmitic acid + oleic acid treatment or vegfb knockdown significantly increased TG and TC contents, promoting lipid droplet deposition in hepatocytes. Vegfb overexpression has the opposite effects, inhibiting lipid deposition and downregulating fatty acid transport and adipogenesis genes. In contrast, the vegfb knockdown significantly upregulated the expression levels of c/ebpα, plin2, and dgat1 (P < 0.05). These results demonstrate that Vegfb may play an important role in reducing lipid deposition by regulating fatty acid transport and adipogenesis in the hepatocytes of spotted sea bass.
Collapse
Affiliation(s)
- Ningning Su
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Jun Zheng
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Guanrong Zhang
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Junfeng Guan
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Xin Gao
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Zhiyi Cheng
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Chao Xu
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Dizhi Xie
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Yuanyou Li
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China.
| |
Collapse
|
|
27
|
Liu B, Yi D, Li S, Ramirez K, Xia X, Cao Y, Zhao H, Tripathi A, Qiu S, Kala M, Rafikov R, Gu H, de jesus Perez V, Lemay SE, Glembotski CC, Knox KS, Bonnet S, Kalinichenko VV, Zhao YY, Fallon MB, Boucherat O, Dai Z. Single-cell and Spatial Transcriptomics Identified Fatty Acid-binding Proteins Controlling Endothelial Glycolytic and Arterial Programming in Pulmonary Hypertension. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.11.579846. [PMID: 38370670 PMCID: PMC10871348 DOI: 10.1101/2024.02.11.579846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Single-cell RNA sequencing (scRNAseq) analysis found that both FABP4 and FABP5 were highly induced in endothelial cells (ECs) of Egln1Tie2Cre (CKO) mice, which was also observed in pulmonary arterial ECs (PAECs) from idiopathic PAH (IPAH) patients, and in whole lungs of pulmonary hypertension (PH) rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters using plasma proteome analysis. Genetic deletion of both Fabp4 and 5 in CKO mice (Egln1Tie2Cre/Fabp4-5-/- ,TKO) caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure assessed by echocardiography, hemodynamic and histological analysis. Employing bulk RNA-seq and scRNA-seq, and spatial transcriptomic analysis, we showed that Fabp4/5 deletion also inhibited EC glycolysis and distal arterial programming, reduced ROS and HIF-2α expression in PH lungs. Thus, PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.
Collapse
Affiliation(s)
- Bin Liu
- Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, AZ, USA
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
- Translational Cardiovascular Research Center, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Dan Yi
- Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, AZ, USA
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
- Translational Cardiovascular Research Center, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Shuai Li
- Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, AZ, USA
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Karina Ramirez
- Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, AZ, USA
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Xiaomei Xia
- Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, AZ, USA
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Yanhong Cao
- Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, AZ, USA
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Hanqiu Zhao
- Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, AZ, USA
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Ankit Tripathi
- Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, AZ, USA
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Shenfeng Qiu
- Translational Cardiovascular Research Center, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Mrinalini Kala
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Ruslan Rafikov
- Department of Medicine, Indiana University College of Medicine, Indianapolis, IN, USA
| | - Haiwei Gu
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | | | - Sarah-Eve Lemay
- Pulmonary Hypertension and Vascular Biology Research Group, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Christopher C. Glembotski
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
- Translational Cardiovascular Research Center, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Kenneth S Knox
- Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, AZ, USA
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Sebastien Bonnet
- Pulmonary Hypertension and Vascular Biology Research Group, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Vladimir V. Kalinichenko
- Division of Neonatology, Phoenix Children’s Hospital, Phoenix, AZ, USA
- Phoenix Children’s Health Research Institute, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - You-Yang Zhao
- Program for Lung and Vascular Biology and Section for Injury Repair and Regeneration Research, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
- Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Michael B. Fallon
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Olivier Boucherat
- Pulmonary Hypertension and Vascular Biology Research Group, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Zhiyu Dai
- Division of Pulmonary, Critical Care and Sleep, University of Arizona, Phoenix, AZ, USA
- Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
- Translational Cardiovascular Research Center, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
- BIO5 Institute, University of Arizona, Tucson, AZ, USA
- Sarver Heart Center, University of Arizona, Tucson, AZ, USA
| |
Collapse
|
|
28
|
Edwards DN, Wang S, Song W, Kim LC, Ngwa VM, Hwang Y, Ess KC, Boothby MR, Chen J. Regulation of fatty acid delivery to metastases by tumor endothelium. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.02.587724. [PMID: 38617241 PMCID: PMC11014634 DOI: 10.1101/2024.04.02.587724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Tumor metastasis, the main cause of death in cancer patients, requires outgrowth of tumor cells after their dissemination and residence in microscopic niches. Nutrient sufficiency is a determinant of such outgrowth1. Fatty acids (FA) can be metabolized by cancer cells for their energetic and anabolic needs but impair the cytotoxicity of T cells in the tumor microenvironment (TME)2,3, thereby supporting metastatic progression. However, despite the important role of FA in metastatic outgrowth, the regulation of intratumoral FA is poorly understood. In this report, we show that tumor endothelium actively promotes tumor growth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. This process uses transendothelial fatty acid transport via endosome cargo trafficking in a mechanism that requires mTORC1 activity. Thus, tumor burden was significantly reduced upon endothelial-specific targeted deletion of Raptor, a unique component of the mTORC1 complex (RptorECKO). In vivo trafficking of a fluorescent palmitic acid analog to tumor cells and T cells was reduced in RptorECKO lung metastatic tumors, which correlated with improved markers of T cell cytotoxicity. Combination of anti-PD1 with RAD001/everolimus, at a low dose that selectively inhibits mTORC1 in endothelial cells4, impaired FA uptake in T cells and reduced metastatic disease, corresponding to improved anti-tumor immunity. These findings describe a novel mechanism of transendothelial fatty acid transfer into the TME during metastatic outgrowth and highlight a target for future development of therapeutic strategies.
Collapse
Affiliation(s)
- Deanna N. Edwards
- Vanderbilt University Medical Center, Department of Medicine, Division of Rheumatology and Immunology, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Shan Wang
- Vanderbilt University Medical Center, Department of Medicine, Division of Rheumatology and Immunology, Nashville, TN, USA
| | - Wenqiang Song
- Vanderbilt University Medical Center, Department of Medicine, Division of Rheumatology and Immunology, Nashville, TN, USA
- Vanderbilt University Medical Center, Department of Medicine, Division of Epidemiology, Nashville, TN, USA
- Vanderbilt University Medical Center, Department of Pathology, Microbiology and Immunology, Nashville, TN, USA
| | - Laura C. Kim
- Vanderbilt University, Program in Cancer Biology, Nashville, TN, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Verra M. Ngwa
- Vanderbilt University Medical Center, Department of Medicine, Division of Rheumatology and Immunology, Nashville, TN, USA
| | - Yoonha Hwang
- Vanderbilt University Medical Center, Department of Medicine, Division of Rheumatology and Immunology, Nashville, TN, USA
| | - Kevin C. Ess
- University of Colorado Anschutz Medical Campus, Department of Pediatrics, Denver, CO, USA
- Vanderbilt University Medical Center, Department of Pediatrics, Nashville, TN, USA
| | - Mark R. Boothby
- Vanderbilt University Medical Center, Department of Medicine, Division of Rheumatology and Immunology, Nashville, TN, USA
- Vanderbilt University Medical Center, Department of Pathology, Microbiology and Immunology, Nashville, TN, USA
- Vanderbilt University, Program in Cancer Biology, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN, USA
| | - Jin Chen
- Vanderbilt University Medical Center, Department of Medicine, Division of Rheumatology and Immunology, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- Vanderbilt University, Program in Cancer Biology, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN, USA
- Vanderbilt University, Department of Cell and Developmental Biology, Nashville, TN, USA
- Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN, USA
| |
Collapse
|
|
29
|
Lechner K, Kia S, von Korn P, Dinges SM, Mueller S, Tjønna AE, Wisløff U, Van Craenenbroeck EM, Pieske B, Adams V, Pressler A, Landmesser U, Halle M, Kränkel N. Cardiometabolic and immune response to exercise training in patients with metabolic syndrome: retrospective analysis of two randomized clinical trials. Front Cardiovasc Med 2024; 11:1329633. [PMID: 38638882 PMCID: PMC11025358 DOI: 10.3389/fcvm.2024.1329633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 03/21/2024] [Indexed: 04/20/2024] Open
Abstract
Background Metabolic syndrome (MetS) is defined by the presence of central obesity plus ≥two metabolic/cardiovascular risk factors (RF), with inflammation being a major disease-driving mechanism. Structured endurance exercise training (ET) may positively affect these traits, as well as cardiorespiratory fitness (V̇O2peak). Aims We explore individual ET-mediated improvements of MetS-associated RF in relation to improvements in V̇O2peak and inflammatory profile. Methods MetS patients from two randomized controlled trials, ExMET (n = 24) and OptimEx (n = 34), had performed 4- or 3-months supervised ET programs according to the respective trial protocol. V̇O2peak, MetS-defining RFs (both RCTs), broad blood leukocyte profile, cytokines and plasma proteins (ExMET only) were assessed at baseline and follow-up. Intra-individual changes in RFs were analysed for both trials separately using non-parametric approaches. Associations between changes in each RF over the exercise period (n-fold of baseline values) were correlated using a non-parametrical approach (Spearman). RF clustering was explored by uniform manifold approximation and projection (UMAP) and changes in RF depending on other RF or exercise parameters were explored by recursive partitioning. Results Four months of ET reduced circulating leukocyte counts (63.5% of baseline, P = 8.0e-6), especially effector subtypes. ET response of MetS-associated RFs differed depending on patients' individual RF constellation, but was not associated with individual change in V̇O2peak. Blood pressure lowering depended on cumulative exercise duration (ExMET: ≥102 min per week; OptimEx-MetS: ≥38 min per session) and baseline triglyceride levels (ExMET: <150 mg/dl; OptimEx-MetS: <174.8 mg/dl). Neuropilin-1 plasma levels were inversely associated with fasting plasma triglycerides (R: -0.4, P = 0.004) and changes of both parameters during the ET phase were inversely correlated (R: -0.7, P = 0.0001). Conclusions ET significantly lowered effector leukocyte blood counts. The improvement of MetS-associated cardiovascular RFs depended on individual basal RF profile and exercise duration but was not associated with exercise-mediated increase in V̇O2peak. Neuropilin-1 may be linked to exercise-mediated triglyceride lowering.
Collapse
Affiliation(s)
- Katharina Lechner
- Department of Prevention and Sports Medicine, University Hospital Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- DZHK, German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
- Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
| | - Sylvia Kia
- Deutsches Herzzentrum der Charité, Klinik für Kardiologie, Angiologie und Intensivmedizin, Berlin, Germany
- DZHK, German Centre for Cardiovascular Research, Partner Site, Berlin, Germany
| | - Pia von Korn
- Department of Prevention and Sports Medicine, University Hospital Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- DZHK, German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
| | - Sophia M. Dinges
- Department of Prevention and Sports Medicine, University Hospital Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- DZHK, German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
| | - Stephan Mueller
- Department of Prevention and Sports Medicine, University Hospital Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- DZHK, German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
| | - Arnt-Erik Tjønna
- Cardiac Exercise Research Group (CERG), Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ulrik Wisløff
- Cardiac Exercise Research Group (CERG), Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, University of Queensland, Brisbane, Queensland, Australia
| | - Emeline M. Van Craenenbroeck
- Research Group Cardiovascular Diseases, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital (UZA), Edegem, Belgium
| | - Burkert Pieske
- Department of Internal Medicine and Cardiology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Volker Adams
- Department of Cardiology and Internal Medicine, Heart Center Dresden-University Hospital, TU Dresden, Dresden, Germany
| | - Axel Pressler
- Department of Prevention and Sports Medicine, University Hospital Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- DZHK, German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
- Private Center for Sports and Exercise Cardiology, Munich, Germany
| | - Ulf Landmesser
- Deutsches Herzzentrum der Charité, Klinik für Kardiologie, Angiologie und Intensivmedizin, Berlin, Germany
- DZHK, German Centre for Cardiovascular Research, Partner Site, Berlin, Germany
- Friede Springer—Centre of Cardiovascular Prevention at Charité, Charité University Medicine Berlin, Berlin, Germany
| | - Martin Halle
- Department of Prevention and Sports Medicine, University Hospital Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- DZHK, German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
| | - Nicolle Kränkel
- Deutsches Herzzentrum der Charité, Klinik für Kardiologie, Angiologie und Intensivmedizin, Berlin, Germany
- DZHK, German Centre for Cardiovascular Research, Partner Site, Berlin, Germany
- Friede Springer—Centre of Cardiovascular Prevention at Charité, Charité University Medicine Berlin, Berlin, Germany
| |
Collapse
|
|
30
|
Zuo B, Yang F, Huang L, Han J, Li T, Ma Z, Cao L, Li Y, Bai X, Jiang M, He Y, Xia L. Endothelial Slc35a1 Deficiency Causes Loss of LSEC Identity and Exacerbates Neonatal Lipid Deposition in the Liver in Mice. Cell Mol Gastroenterol Hepatol 2024; 17:1039-1061. [PMID: 38467191 PMCID: PMC11061248 DOI: 10.1016/j.jcmgh.2024.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 03/13/2024]
Abstract
BACKGROUND & AIMS The functional maturation of the liver largely occurs after birth. In the early stages of life, the liver of a newborn encounters enormous high-fat metabolic stress caused by the consumption of breast milk. It is unclear how the maturing liver adapts to high lipid metabolism. Liver sinusoidal endothelial cells (LSECs) play a fundamental role in establishing liver vasculature and are decorated with many glycoproteins on their surface. The Slc35a1 gene encodes a cytidine-5'-monophosphate (CMP)-sialic acid transporter responsible for transporting CMP-sialic acids between the cytoplasm and the Golgi apparatus for protein sialylation. This study aimed to determine whether endothelial sialylation plays a role in hepatic vasculogenesis and functional maturation. METHODS Endothelial-specific Slc35a1 knockout mice were generated. Liver tissues were collected for histologic analysis, lipidomic profiling, RNA sequencing, confocal immunofluorescence, and immunoblot analyses. RESULTS Endothelial Slc35a1-deficient mice exhibited excessive neonatal hepatic lipid deposition, severe liver damage, and high mortality. Endothelial deletion of Slc35a1 led to sinusoidal capillarization and disrupted hepatic zonation. Mechanistically, vascular endothelial growth factor receptor 2 (VEGFR2) in LSECs was desialylated and VEGFR2 signaling was enhanced in Slc35a1-deficient mice. Inhibition of VEGFR2 signaling by SU5416 alleviated lipid deposition and restored hepatic vasculature in Slc35a1-deficient mice. CONCLUSIONS Our findings suggest that sialylation of LSECs is critical for maintaining hepatic vascular development and lipid homeostasis. Targeting VEGFR2 signaling may be a new strategy to prevent liver disorders associated with abnormal vasculature and lipid deposition.
Collapse
Affiliation(s)
- Bin Zuo
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Engineering Center of Hematological Disease of Ministry of Education, Cyrus Tang Hematology Center, Soochow University, Suzhou, China
| | - Fei Yang
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lulu Huang
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jingjing Han
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Tianyi Li
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhenni Ma
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lijuan Cao
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yun Li
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xia Bai
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Miao Jiang
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yang He
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Engineering Center of Hematological Disease of Ministry of Education, Cyrus Tang Hematology Center, Soochow University, Suzhou, China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
| | - Lijun Xia
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
| |
Collapse
|
|
31
|
Hu S, Hang X, Wei Y, Wang H, Zhang L, Zhao L. Crosstalk among podocytes, glomerular endothelial cells and mesangial cells in diabetic kidney disease: an updated review. Cell Commun Signal 2024; 22:136. [PMID: 38374141 PMCID: PMC10875896 DOI: 10.1186/s12964-024-01502-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 01/28/2024] [Indexed: 02/21/2024] Open
Abstract
Diabetic kidney disease (DKD) is a long-term and serious complication of diabetes that affects millions of people worldwide. It is characterized by proteinuria, glomerular damage, and renal fibrosis, leading to end-stage renal disease, and the pathogenesis is complex and involves multiple cellular and molecular mechanisms. Among three kinds of intraglomerular cells including podocytes, glomerular endothelial cells (GECs) and mesangial cells (MCs), the alterations in one cell type can produce changes in the others. The cell-to-cell crosstalk plays a crucial role in maintaining the glomerular filtration barrier (GFB) and homeostasis. In this review, we summarized the recent advances in understanding the pathological changes and interactions of these three types of cells in DKD and then focused on the signaling pathways and factors that mediate the crosstalk, such as angiopoietins, vascular endothelial growth factors, transforming growth factor-β, Krüppel-like factors, retinoic acid receptor response protein 1 and exosomes, etc. Furthermore, we also simply introduce the application of the latest technologies in studying cell interactions within glomerular cells and new promising mediators for cell crosstalk in DKD. In conclusion, this review provides a comprehensive and updated overview of the glomerular crosstalk in DKD and highlights its importance for the development of novel intervention approaches.
Collapse
Affiliation(s)
- Shiwan Hu
- Institute of Metabolic Diseases, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xing Hang
- Institute of Metabolic Diseases, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yu Wei
- Institute of Metabolic Diseases, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Han Wang
- Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Lili Zhang
- Institute of Metabolic Diseases, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
| | - Linhua Zhao
- Institute of Metabolic Diseases, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
| |
Collapse
|
|
32
|
Cleveland AH, Fan Y. Reprogramming endothelial cells to empower cancer immunotherapy. Trends Mol Med 2024; 30:126-135. [PMID: 38040601 PMCID: PMC10922198 DOI: 10.1016/j.molmed.2023.11.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/05/2023] [Accepted: 11/06/2023] [Indexed: 12/03/2023]
Abstract
Cancer immunity is subject to spatiotemporal regulation by leukocyte interaction with the tumor microenvironment. Growing evidence suggests an emerging role for the vasculature in tumor immune evasion and immunotherapy resistance. Beyond the conventional functions of the tumor vasculature, such as providing oxygen and nutrients to support tumor progression, we propose multiplex mechanisms for vascular regulation of tumor immunity: The immunosuppressive vascular niche locoregionally educates circulation-derived immune cells by angiocrines, aberrant endothelial metabolism induces T cell exclusion and inactivation, and topologically and biochemically abnormal vascularity forms a pathophysiological barrier that hampers lymphocyte infiltration. We postulate that genetic and metabolic reprogramming of endothelial cells may rewire the immunosuppressive vascular microenvironment to overcome immunotherapy resistance, serving as a next-generation vascular targeting strategy for cancer treatment.
Collapse
Affiliation(s)
- Abigail H Cleveland
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Yi Fan
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
33
|
Vora N, Patel P, Gajjar A, Ladani P, Konat A, Bhanderi D, Gadam S, Prajjwal P, Sharma K, Arunachalam SP. Gene therapy for heart failure: A novel treatment for the age old disease. Dis Mon 2024; 70:101636. [PMID: 37734966 DOI: 10.1016/j.disamonth.2023.101636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/23/2023]
Abstract
Across the globe, cardiovascular disease (CVD) is the leading cause of mortality. According to reports, around 6.2 million people in the United states have heart failure. Current standards of care for heart failure can delay but not prevent progression of disease. Gene therapy is one of the novel treatment modalities that promises to fill this limitation in the current standard of care for Heart Failure. In this paper we performed an extensive search of the literature on various advances made in gene therapy for heart failure till date. We review the delivery methods, targets, current applications, trials, limitations and feasibility of gene therapy for heart failure. Various methods have been employed till date for administering gene therapies including but not limited to arterial and venous infusion, direct myocardial injection and pericardial injection. Various strategies such as AC6 expression, S100A1 protein upregulation, VEGF-B and SDF-1 gene therapy have shown promise in recent preclinical trials. Furthermore, few studies even show that stimulation of cardiomyocyte proliferation such as through cyclin A2 overexpression is a realistic avenue. However, a considerable number of obstacles need to be overcome for gene therapy to be part of standard treatment of care such as definitive choice of gene, gene delivery systems and a suitable method for preclinical trials and clinical trials on patients. Considering the challenges and taking into account the recent advances in gene therapy research, there are encouraging signs to indicate gene therapy for heart failure to be a promising treatment modality for the future. However, the time and feasibility of this option remains in a situation of balance.
Collapse
Affiliation(s)
- Neel Vora
- B. J. Medical College, Ahmedabad, India
| | - Parth Patel
- Pramukhswami Medical College, Karamsad, India
| | | | | | - Ashwati Konat
- University School of Sciences, Gujarat University, Ahmedabad, India
| | | | | | | | - Kamal Sharma
- U. N. Mehta Institute of Cardiology and Research Centre, Ahmedabad, India.
| | | |
Collapse
|
|
34
|
Zhang S, Tian W, Duan X, Zhang Q, Cao L, Liu C, Li G, Wang Z, Zhang J, Li J, Yang L, Gao Y, Xu Y, Liu J, Yan J, Cui J, Feng L, Liu C, Shen Y, Qi Z. Melatonin attenuates diabetic cardiomyopathy by increasing autophagy of cardiomyocytes via regulation of VEGF-B/GRP78/PERK signaling pathway. Cardiovasc Diabetol 2024; 23:19. [PMID: 38195474 PMCID: PMC10777497 DOI: 10.1186/s12933-023-02078-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 11/27/2023] [Indexed: 01/11/2024] Open
Abstract
AIMS Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. METHODS AND RESULTS We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B-/- mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. CONCLUSIONS These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.
Collapse
Affiliation(s)
- Shengzheng Zhang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Wencong Tian
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China
| | - Xianxian Duan
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Qian Zhang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Lei Cao
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China
| | - Chunlei Liu
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Guangru Li
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Ziwei Wang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Junwei Zhang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jing Li
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Liang Yang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China
| | - Yang Gao
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China
| | - Yang Xu
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jie Liu
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jie Yan
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jianlin Cui
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Lifeng Feng
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Chang Liu
- School of Medical Technology, Tianjin Medical University, Tianjin, 300203, China
- Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, 571199, China
| | - Yanna Shen
- School of Medical Technology, Tianjin Medical University, Tianjin, 300203, China.
- Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, 571199, China.
| | - Zhi Qi
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China.
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China.
- Xinjiang Production and Construction Corps Hospital, Xinjiang, 830092, China.
| |
Collapse
|
|
35
|
Boutagy NE, Gamez-Mendez A, Fowler JW, Zhang H, Chaube BK, Esplugues E, Kuo A, Lee S, Horikami D, Zhang J, Citrin KM, Singh AK, Coon BG, Lee MY, Suarez Y, Fernandez-Hernando C, Sessa WC. Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice. J Clin Invest 2024; 134:e170453. [PMID: 38175710 PMCID: PMC10866653 DOI: 10.1172/jci170453] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024] Open
Abstract
Blood vessels are continually exposed to circulating lipids, and elevation of ApoB-containing lipoproteins causes atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FAs) into triglyceride-rich (TG-rich) lipid droplets (LDs) is not known. In this study, we showed that deletion of the enzyme adipose TG lipase (ATGL) in the endothelium led to neutral lipid accumulation in vessels and impaired endothelial-dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL led to endoplasmic reticulum stress-induced inflammation in the endothelium. Consistent with this mechanism, deletion of endothelial ATGL markedly increased lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD affects endothelial cell homeostasis and consequently large vessel function during normal physiology and in a chronic disease state.
Collapse
Affiliation(s)
- Nabil E. Boutagy
- Department of Pharmacology
- Vascular Biology and Therapeutics Program, and
| | - Ana Gamez-Mendez
- Department of Pharmacology
- Vascular Biology and Therapeutics Program, and
| | - Joseph W.M. Fowler
- Department of Pharmacology
- Vascular Biology and Therapeutics Program, and
| | - Hanming Zhang
- Vascular Biology and Therapeutics Program, and
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Bal K. Chaube
- Vascular Biology and Therapeutics Program, and
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Enric Esplugues
- Vascular Biology and Therapeutics Program, and
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Andrew Kuo
- Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Sungwoon Lee
- Department of Pharmacology
- Vascular Biology and Therapeutics Program, and
| | - Daiki Horikami
- Department of Pharmacology
- Vascular Biology and Therapeutics Program, and
| | - Jiasheng Zhang
- Department of Cardiology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Kathryn M. Citrin
- Vascular Biology and Therapeutics Program, and
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Abhishek K. Singh
- Department of Pharmacology
- Vascular Biology and Therapeutics Program, and
| | - Brian G. Coon
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Monica Y. Lee
- Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago School of Medicine, Chicago, Illinois, USA
| | - Yajaira Suarez
- Vascular Biology and Therapeutics Program, and
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Carlos Fernandez-Hernando
- Vascular Biology and Therapeutics Program, and
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - William C. Sessa
- Department of Pharmacology
- Vascular Biology and Therapeutics Program, and
- Department of Cardiology, Yale University School of Medicine, New Haven, Connecticut, USA
| |
Collapse
|
|
36
|
Shang R, Lee CS, Wang H, Dyer R, Noll C, Carpentier A, Sultan I, Alitalo K, Boushel R, Hussein B, Rodrigues B. Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization. Arterioscler Thromb Vasc Biol 2024; 44:177-191. [PMID: 38150518 DOI: 10.1161/atvbaha.123.319972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/06/2023] [Indexed: 12/29/2023]
Abstract
BACKGROUND The heart relies heavily on external fatty acid (FA) for energy production. VEGFB (vascular endothelial growth factor B) has been shown to promote endothelial FA uptake by upregulating FA transporters. However, its impact on LPL (lipoprotein lipase)-mediated lipolysis of lipoproteins, a major source of FA for cardiac use, is unknown. METHODS VEGFB transgenic (Tg) rats were generated by using the α-myosin heavy chain promoter to drive cardiomyocyte-specific overexpression. To measure coronary LPL activity, Langendorff hearts were perfused with heparin. In vivo positron emission tomography imaging with [18F]-triglyceride-fluoro-6-thia-heptadecanoic acid and [11C]-palmitate was used to determine cardiac FA uptake. Mitochondrial FA oxidation was evaluated by high-resolution respirometry. Streptozotocin was used to induce diabetes, and cardiac function was monitored using echocardiography. RESULTS In Tg hearts, the vectorial transfer of LPL to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes, an effect likely due to coronary vascular development with its associated augmentation of insulin action. With insulin insufficiency following fasting, VEGFB acted unimpeded to facilitate LPL movement and increase its activity at the coronary lumen. In vivo PET imaging following fasting confirmed that VEGFB induced a greater FA uptake to the heart from circulating lipoproteins as compared with plasma-free FAs. As this was associated with augmented mitochondrial oxidation, lipid accumulation in the heart was prevented. We further examined whether this property of VEGFB on cardiac metabolism could be useful following diabetes and its associated cardiac dysfunction, with attendant loss of metabolic flexibility. In Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling, effects that could explain its lack of cardioprotection. CONCLUSIONS Our study highlights the novel role of VEGFB in LPL-derived FA supply and utilization. In diabetes, loss of VEGFB action may contribute toward metabolic inflexibility, lipotoxicity, and development of diabetic cardiomyopathy.
Collapse
Affiliation(s)
- Rui Shang
- Faculty of Pharmaceutical Sciences (R.S., C.S.L., H.W., B.H., B.R.), University of British Columbia, Vancouver
| | - Chae Syng Lee
- Faculty of Pharmaceutical Sciences (R.S., C.S.L., H.W., B.H., B.R.), University of British Columbia, Vancouver
| | - Hualin Wang
- Faculty of Pharmaceutical Sciences (R.S., C.S.L., H.W., B.H., B.R.), University of British Columbia, Vancouver
| | - Roger Dyer
- Department of Pediatrics (R.D.), University of British Columbia, Vancouver
| | - Christophe Noll
- Department of Medicine, Université de Sherbrooke, QC, Canada (C.N., A.C.)
| | - André Carpentier
- Department of Medicine, Université de Sherbrooke, QC, Canada (C.N., A.C.)
| | - Ibrahim Sultan
- Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Finland (I.S., K.A.)
| | - Kari Alitalo
- Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Finland (I.S., K.A.)
| | - Robert Boushel
- School of Kinesiology (R.B.), University of British Columbia, Vancouver
| | - Bahira Hussein
- Faculty of Pharmaceutical Sciences (R.S., C.S.L., H.W., B.H., B.R.), University of British Columbia, Vancouver
| | - Brian Rodrigues
- Faculty of Pharmaceutical Sciences (R.S., C.S.L., H.W., B.H., B.R.), University of British Columbia, Vancouver
| |
Collapse
|
|
37
|
Dlamini M, Khathi A. Prediabetes-Associated Changes in Skeletal Muscle Function and Their Possible Links with Diabetes: A Literature Review. Int J Mol Sci 2023; 25:469. [PMID: 38203642 PMCID: PMC10778616 DOI: 10.3390/ijms25010469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
The skeletal muscle plays a critical role in regulating systemic blood glucose homeostasis. Impaired skeletal muscle glucose homeostasis associated with type 2 diabetes mellitus (T2DM) has been observed to significantly affect the whole-body glucose homeostasis, thereby resulting in other diabetic complications. T2DM does not only affect skeletal muscle glucose homeostasis, but it also affects skeletal muscle structure and functional capacity. Given that T2DM is a global health burden, there is an urgent need to develop therapeutic medical therapies that will aid in the management of T2DM. Prediabetes (PreDM) is a prominent risk factor of T2DM that usually goes unnoticed in many individuals as it is an asymptomatic condition. Hence, research on PreDM is essential because establishing diabetic biomarkers during the prediabetic state would aid in preventing the development of T2DM, as PreDM is a reversible condition if it is detected in the early stages. The literature predominantly documents the changes in skeletal muscle during T2DM, but the changes in skeletal muscle during prediabetes are not well elucidated. In this review, we seek to review the existing literature on PreDM- and T2DM-associated changes in skeletal muscle function.
Collapse
Affiliation(s)
| | - Andile Khathi
- Department of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban X54001, South Africa;
| |
Collapse
|
|
38
|
Parvaneh RR, Vajdi M, Shiraz AN, Khani M, Farshbaf SE, Farhangi MA. Prognostic value of circulating macrophage inhibitory cytokine 1-growth differentiation factor 15 (MIC-1/GDF15) in obesity: Relation with vascular endothelial growth factor (VEGF) and markers of oxidative stress. Nutr Health 2023; 29:707-713. [PMID: 35549472 DOI: 10.1177/02601060221099716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: Macrophage inhibitory cytokine 1-Growth differentiation Factor 15 (MIC-1/GDF15) and vascular endothelial growth factor (VEGF) are novel regulators of obesity and energy homeostasis and food intake. Aims: In the current cross-sectional study, we aimed to evaluate MIC-1 and VEGF concentrations and their association with serum lipids and biomarkers of oxidative stress in obese individuals. Methods: Fifty six obese subjects, aged between 20-50 years old, participated in the current study. Anthropometric and nutritional parameters were assessed and serum and blood concentrations of MIC-1/GDF15, VEGF, markers of oxidative stress and serum lipids were evaluated. Results: Serum VEGF was strongly associated with serum lipids and MIC-1/GDF15 concentrations while serum MIC-1/GDF15 was associated with total cholesterol (TC) and VEGF levels. In multivariate regression analysis, serum VEGF, appetite and GPX were potent determinants of MIC-1/GDF15 concentrations while VEGF was only associated with serum MIC-1/GDF15. Conclusion: The findings of the current study demonstrated the association between MIC-1/GDF15 and VEGF. Moreover, a positive association between these cytokines and serum lipids, was also observed. The results suggest that MIC-1/GDF15 and VEGF might be considered as prognostic markers in obesity-related metabolic disorders. Although further mechanistic studies are needed to better clarify the underlying mechanism.
Collapse
Affiliation(s)
- Roghayeh Rahbar Parvaneh
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahdi Vajdi
- Department of Community Nutrition, Faculty of Nutrition, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ata Nikfam Shiraz
- School of Nursing and Midwifery, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Khani
- Department of Community Nutrition, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sara Ebadpour Farshbaf
- Department of Community Nutrition, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran
| | | |
Collapse
|
|
39
|
Madonna R. Endothelial heterogeneity and their relevance in cardiac development and coronary artery disease. Vascul Pharmacol 2023; 153:107242. [PMID: 37940065 DOI: 10.1016/j.vph.2023.107242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/30/2023] [Accepted: 11/04/2023] [Indexed: 11/10/2023]
Abstract
Micro- and macrovascular endothelial cells (ECs) are characterized by structural and functional heterogeneity, which is also reflected in their secretory activity. The root of this heterogeneity and related regulatory mechanisms are still poorly understood. During embryogenesis, microvascular ECs participate in organogenesis prior to the development of the fetal circulation, suggesting that ECs are capable of releasing paracrine trophogens, termed angiocrine factors (AFs). These are angiocrine growth factors, adhesion molecules, and chemokines, which are intended to promote morphogenesis and repair of the adjacent parenchyma/stroma where the vessels are located. There is a tissue and organ-specificity of AFs that traces the heterogeneity of ECs. This AF heterogeneity also traces how ECs respond to pathological conditions or exposure to cardiovascular risk factors. The study of the mechanisms that regulate endothelial and paracrine heterogeneity and that contribute to endotheliopathy represents a broad and as yet understudied area of research. A better understanding of the cellular and molecular mechanisms that regulate this heterogeneity, leading to endotheliopathy is an exciting challenge. In this brief review we will discuss experimental advances in the heterogeneity of ECs and their AF, with a focus on their involvement in the pathogenesis of coronary artery disease.
Collapse
Affiliation(s)
- Rosalinda Madonna
- Cardiology Division, Department of Pathology, University of Pisa, Via Paradisa, 56124 Pisa, Italy.
| |
Collapse
|
|
40
|
Li YQ, Zhang LY, Zhao YC, Xu F, Hu ZY, Wu QH, Li WH, Li YN. Vascular endothelial growth factor B improves impaired glucose tolerance through insulin-mediated inhibition of glucagon secretion. World J Diabetes 2023; 14:1643-1658. [DOI: 10.4239/wjd.v14.i11.1643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/11/2023] [Accepted: 09/06/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Impaired glucose tolerance (IGT) is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes. When IGT occurs, insulin sensitivity decreases, causing a reduction in insulin secretion and an increase in glucagon secretion. Recently, vascular endothelial growth factor B (VEGFB) has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity. Therefore, we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion, thus contributing to the prevention and cure of prediabetes.
AIM To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT.
METHODS We conducted in vivo experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression. Insulin and glucagon secretions were detected via enzyme-linked immunosorbent assay, and the protein expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) was determined using western blot. Further, mRNA expression of forkhead box protein O1, phosphoenolpyruvate carboxykinase, and glucose-6 phosphatase was detected via quantitative polymerase chain reaction, and the correlation between the expression of proteins was analyzed via bioinformatics.
RESULTS In mice with IGT and VEGFB knockout, glucagon secretion increased, and the protein expression of PI3K/AKT decreased dramatically. Further, in mice with VEGFB overexpression, glucagon levels declined, with the activation of the PI3K/AKT signaling pathway.
CONCLUSION VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.
Collapse
Affiliation(s)
- Yu-Qi Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Lu-Yang Zhang
- Department of Rheumatology and Immunology, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Fang Xu
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Zhi-Yong Hu
- School of Public Health and Management, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Qi-Hao Wu
- The First School of Clinical Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Wen-Hao Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Ya-Nuo Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| |
Collapse
|
|
41
|
Cheng YC, Hsieh ML, Lin CJ, Chang CMC, Huang CY, Puntney R, Wu Moy A, Ting CY, Herr Chan DZ, Nicholson MW, Lin PJ, Chen HC, Kim GC, Zhang J, Coonen J, Basu P, Simmons HA, Liu YW, Hacker TA, Kamp TJ, Hsieh PCH. Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates. Circulation 2023; 148:1395-1409. [PMID: 37732466 PMCID: PMC10683868 DOI: 10.1161/circulationaha.122.061736] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/23/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs. METHODS We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated. RESULTS We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion. CONCLUSIONS These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.
Collapse
Affiliation(s)
- Yu-Che Cheng
- Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)
| | - Marvin L Hsieh
- Model Organisms Research Core, Department of Medicine (M.L.H., C.M.C.C., T.A.H.), University of Wisconsin-Madison
| | - Chen-Ju Lin
- Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)
| | - Cindy M C Chang
- Model Organisms Research Core, Department of Medicine (M.L.H., C.M.C.C., T.A.H.), University of Wisconsin-Madison
| | - Ching-Ying Huang
- Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)
| | - Riley Puntney
- Wisconsin National Primate Research Center (R.P., A.W.M., J.C., P.B., H.A.S.), University of Wisconsin-Madison
| | - Amy Wu Moy
- Wisconsin National Primate Research Center (R.P., A.W.M., J.C., P.B., H.A.S.), University of Wisconsin-Madison
| | - Chien-Yu Ting
- Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)
| | - Darien Zhing Herr Chan
- Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)
| | - Martin W Nicholson
- Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)
| | - Po-Ju Lin
- Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)
| | - Hung-Chih Chen
- Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)
| | - Gina C Kim
- Department of Medicine and Stem Cell and Regenerative Medicine Center (G.C.K., J.Z., T.J.K., P.C.H.H.), University of Wisconsin-Madison
| | - Jianhua Zhang
- Department of Medicine and Stem Cell and Regenerative Medicine Center (G.C.K., J.Z., T.J.K., P.C.H.H.), University of Wisconsin-Madison
| | - Jennifer Coonen
- Wisconsin National Primate Research Center (R.P., A.W.M., J.C., P.B., H.A.S.), University of Wisconsin-Madison
| | - Puja Basu
- Wisconsin National Primate Research Center (R.P., A.W.M., J.C., P.B., H.A.S.), University of Wisconsin-Madison
| | - Heather A Simmons
- Wisconsin National Primate Research Center (R.P., A.W.M., J.C., P.B., H.A.S.), University of Wisconsin-Madison
| | - Yen-Wen Liu
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan (Y.W.L.)
| | - Timothy A Hacker
- Model Organisms Research Core, Department of Medicine (M.L.H., C.M.C.C., T.A.H.), University of Wisconsin-Madison
| | - Timothy J Kamp
- Department of Medicine and Stem Cell and Regenerative Medicine Center (G.C.K., J.Z., T.J.K., P.C.H.H.), University of Wisconsin-Madison
| | - Patrick C H Hsieh
- Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)
- Department of Medicine and Stem Cell and Regenerative Medicine Center (G.C.K., J.Z., T.J.K., P.C.H.H.), University of Wisconsin-Madison
- Institute of Medical Genomics and Proteomics and Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan (P.C.H.H.)
| |
Collapse
|
|
42
|
Chen C, Wang J, Liu C, Hu J, Liu L. Pioneering therapies for post-infarction angiogenesis: Insight into molecular mechanisms and preclinical studies. Biomed Pharmacother 2023; 166:115306. [PMID: 37572633 DOI: 10.1016/j.biopha.2023.115306] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/01/2023] [Accepted: 08/07/2023] [Indexed: 08/14/2023] Open
Abstract
Acute myocardial infarction (MI), despite significant progress in its treatment, remains a leading cause of chronic heart failure and cardiovascular events such as cardiac arrest. Promoting angiogenesis in the myocardial tissue after MI to restore blood flow in the ischemic and hypoxic tissue is considered an effective treatment strategy. The repair of the myocardial tissue post-MI involves a robust angiogenic response, with mechanisms involved including endothelial cell proliferation and migration, capillary growth, changes in the extracellular matrix, and stabilization of pericytes for neovascularization. In this review, we provide a detailed overview of six key pathways in angiogenesis post-MI: the PI3K/Akt/mTOR signaling pathway, the Notch signaling pathway, the Wnt/β-catenin signaling pathway, the Hippo signaling pathway, the Sonic Hedgehog signaling pathway, and the JAK/STAT signaling pathway. We also discuss novel therapeutic approaches targeting these pathways, including drug therapy, gene therapy, protein therapy, cell therapy, and extracellular vesicle therapy. A comprehensive understanding of these key pathways and their targeted therapies will aid in our understanding of the pathological and physiological mechanisms of angiogenesis after MI and the development and application of new treatment strategies.
Collapse
Affiliation(s)
- Cong Chen
- Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Jie Wang
- Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China.
| | - Chao Liu
- Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Jun Hu
- Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Lanchun Liu
- Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| |
Collapse
|
|
43
|
Lee-Rueckert M, Canyelles M, Tondo M, Rotllan N, Kovanen PT, Llorente-Cortes V, Escolà-Gil JC. Obesity-induced changes in cancer cells and their microenvironment: Mechanisms and therapeutic perspectives to manage dysregulated lipid metabolism. Semin Cancer Biol 2023; 93:36-51. [PMID: 37156344 DOI: 10.1016/j.semcancer.2023.05.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/05/2023] [Accepted: 05/05/2023] [Indexed: 05/10/2023]
Abstract
Obesity has been closely related to cancer progression, recurrence, metastasis, and treatment resistance. We aim to review recent progress in the knowledge on the obese macroenvironment and the generated adipose tumor microenvironment (TME) inducing lipid metabolic dysregulation and their influence on carcinogenic processes. Visceral white adipose tissue expansion during obesity exerts systemic or macroenvironmental effects on tumor initiation, growth, and invasion by promoting inflammation, hyperinsulinemia, growth-factor release, and dyslipidemia. The dynamic relationship between cancer and stromal cells of the obese adipose TME is critical for cancer cell survival and proliferation as well. Experimental evidence shows that secreted paracrine signals from cancer cells can induce lipolysis in cancer-associated adipocytes, causing them to release free fatty acids and acquire a fibroblast-like phenotype. Such adipocyte delipidation and phenotypic change is accompanied by an increased secretion of cytokines by cancer-associated adipocytes and tumor-associated macrophages in the TME. Mechanistically, the availability of adipose TME free fatty acids and tumorigenic cytokines concomitant with the activation of angiogenic processes creates an environment that favors a shift in the cancer cells toward an aggressive phenotype associated with increased invasiveness. We conclude that restoring the aberrant metabolic alterations in the host macroenvironment and in adipose TME of obese subjects would be a therapeutic option to prevent cancer development. Several dietary, lipid-based, and oral antidiabetic pharmacological therapies could potentially prevent tumorigenic processes associated with the dysregulated lipid metabolism closely linked to obesity.
Collapse
Affiliation(s)
| | - Marina Canyelles
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Mireia Tondo
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Noemi Rotllan
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | | | - Vicenta Llorente-Cortes
- Wihuri Research Institute, Helsinki, Finland; Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), Barcelona, Spain; CIBERCV, Institute of Health Carlos III, 28029 Madrid, Spain.
| | - Joan Carles Escolà-Gil
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
| |
Collapse
|
|
44
|
Lother A, Kohl P. The heterocellular heart: identities, interactions, and implications for cardiology. Basic Res Cardiol 2023; 118:30. [PMID: 37495826 PMCID: PMC10371928 DOI: 10.1007/s00395-023-01000-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/17/2023] [Accepted: 07/17/2023] [Indexed: 07/28/2023]
Abstract
The heterocellular nature of the heart has been receiving increasing attention in recent years. In addition to cardiomyocytes as the prototypical cell type of the heart, non-myocytes such as endothelial cells, fibroblasts, or immune cells are coming more into focus. The rise of single-cell sequencing technologies enables identification of ever more subtle differences and has reignited the question of what defines a cell's identity. Here we provide an overview of the major cardiac cell types, describe their roles in homeostasis, and outline recent findings on non-canonical functions that may be of relevance for cardiology. We highlight modes of biochemical and biophysical interactions between different cardiac cell types and discuss the potential implications of the heterocellular nature of the heart for basic research and therapeutic interventions.
Collapse
Affiliation(s)
- Achim Lother
- Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Albertstr. 25, 79104, Freiburg, Germany.
- Interdisciplinary Medical Intensive Care, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany.
| | - Peter Kohl
- Institute for Experimental Cardiovascular Medicine, Faculty of Medicine, University Heart Center, University of Freiburg, Freiburg, Germany
- CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| |
Collapse
|
|
45
|
Brenmoehl J, Brosig E, Trakooljul N, Walz C, Ohde D, Noce A, Walz M, Langhammer M, Petkov S, Röntgen M, Maak S, Galuska CE, Fuchs B, Kuhla B, Ponsuksili S, Wimmers K, Hoeflich A. Metabolic Pathway Modeling in Muscle of Male Marathon Mice (DUhTP) and Controls (DUC)-A Possible Role of Lactate Dehydrogenase in Metabolic Flexibility. Cells 2023; 12:1925. [PMID: 37566003 PMCID: PMC10417281 DOI: 10.3390/cells12151925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/18/2023] [Accepted: 07/21/2023] [Indexed: 08/12/2023] Open
Abstract
In contracting muscles, carbohydrates and fatty acids serve as energy substrates; the predominant utilization depends on the workload. Here, we investigated the contribution of non-mitochondrial and mitochondrial metabolic pathways in response to repeated training in a polygenic, paternally selected marathon mouse model (DUhTP), characterized by exceptional running performance and an unselected control (DUC), with both lines descended from the same genetic background. Both lines underwent three weeks of high-speed treadmill training or were sedentary. Both lines' muscles and plasma were analyzed. Muscle RNA was sequenced, and KEGG pathway analysis was performed. Analyses of muscle revealed no significant selection-related differences in muscle structure. However, in response to physical exercise, glucose and fatty acid oxidation were stimulated, lactate dehydrogenase activity was reduced, and lactate formation was inhibited in the marathon mice compared with trained control mice. The lack of lactate formation in response to exercise appears to be associated with increased lipid mobilization from peripheral adipose tissue in DUhTP mice, suggesting a specific benefit of lactate avoidance. Thus, results from the analysis of muscle metabolism in born marathon mice, shaped by 35 years (140 generations) of phenotype selection for superior running performance, suggest increased metabolic flexibility in male marathon mice toward lipid catabolism regulated by lactate dehydrogenase.
Collapse
Affiliation(s)
- Julia Brenmoehl
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Elli Brosig
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
- Department of Neurology, Neuroimmunological Section, University Medicine Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
| | - Nares Trakooljul
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Christina Walz
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Daniela Ohde
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Antonia Noce
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
- Department of Animal Genomics, Centre for Research in Agricultural Genomics (CRAG), Campus de la Universitat Autònoma de Barcelona, 08193 Cerdanyola, Spain
| | - Michael Walz
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Martina Langhammer
- Lab Animal Facility, Institute of Genetics and Biometry, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Stefan Petkov
- Institute of Muscle Biology and Growth, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Monika Röntgen
- Institute of Muscle Biology and Growth, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Steffen Maak
- Institute of Muscle Biology and Growth, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Christina E. Galuska
- Core Facility Metabolomics, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Beate Fuchs
- Core Facility Metabolomics, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Björn Kuhla
- Institute of Nutrition, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Siriluck Ponsuksili
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Klaus Wimmers
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | - Andreas Hoeflich
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| |
Collapse
|
|
46
|
Katsi V, Papakonstantinou I, Tsioufis K. Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management. Int J Mol Sci 2023; 24:11786. [PMID: 37511551 PMCID: PMC10381022 DOI: 10.3390/ijms241411786] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/03/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
The involvement of cardiovascular disease in cancer onset and development represents a contemporary interest in basic science. It has been recognized, from the most recent research, that metabolic syndrome-related conditions, ranging from atherosclerosis to diabetes, elicit many pathways regulating lipid metabolism and lipid signaling that are also linked to the same framework of multiple potential mechanisms for inducing cancer. Otherwise, dyslipidemia and endothelial cell dysfunction in atherosclerosis may present common or even interdependent changes, similar to oncogenic molecules elevated in many forms of cancer. However, whether endothelial cell dysfunction in atherosclerotic disease provides signals that promote the pre-clinical onset and proliferation of malignant cells is an issue that requires further understanding, even though more questions are presented with every answer. Here, we highlight the molecular mechanisms that point to a causal link between lipid metabolism and glucose homeostasis in metabolic syndrome-related atherosclerotic disease with the development of cancer. The knowledge of these breakthrough mechanisms may pave the way for the application of new therapeutic targets and for implementing interventions in clinical practice.
Collapse
Affiliation(s)
- Vasiliki Katsi
- Department of Cardiology, Hippokration Hospital, 11527 Athens, Greece
| | | | - Konstantinos Tsioufis
- Department of Cardiology, Hippokration Hospital, 11527 Athens, Greece
- School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| |
Collapse
|
|
47
|
Samuelsson AM, Bartolomaeus TUP, Anandakumar H, Thowsen I, Nikpey E, Han J, Marko L, Finne K, Tenstad O, Eckstein J, Berndt N, Kühne T, Kedziora S, Sultan I, Skogstrand T, Karlsen TV, Nurmi H, Forslund SK, Bollano E, Alitalo K, Muller DN, Wiig H. VEGF-B hypertrophy predisposes to transition from diastolic to systolic heart failure in hypertensive rats. Cardiovasc Res 2023; 119:1553-1567. [PMID: 36951047 PMCID: PMC10318391 DOI: 10.1093/cvr/cvad040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 10/04/2022] [Accepted: 01/10/2023] [Indexed: 03/24/2023] Open
Abstract
AIMS Cardiac energy metabolism is centrally involved in heart failure (HF), although the direction of the metabolic alterations is complex and likely dependent on the particular stage of HF progression. Vascular endothelial growth factor B (VEGF-B) has been shown to modulate metabolic processes and to induce physiological cardiac hypertrophy; thus, it could be cardioprotective in the failing myocardium. This study investigates the role of VEGF-B in cardiac proteomic and metabolic adaptation in HF during aldosterone and high-salt hypertensive challenges. METHODS AND RESULTS Male rats overexpressing the cardiac-specific VEGF-B transgene (VEGF-B TG) were treated for 3 or 6 weeks with deoxycorticosterone-acetate combined with a high-salt (HS) diet (DOCA + HS) to induce hypertension and cardiac damage. Extensive longitudinal echocardiographic studies of HF progression were conducted, starting at baseline. Sham-treated rats served as controls. To evaluate the metabolic alterations associated with HF, cardiac proteomics by mass spectrometry was performed. Hypertrophic non-treated VEGF-B TG hearts demonstrated high oxygen and adenosine triphosphate (ATP) demand with early onset of diastolic dysfunction. Administration of DOCA + HS to VEGF-B TG rats for 6 weeks amplified the progression from cardiac hypertrophy to HF, with a drastic drop in heart ATP concentration. Dobutamine stress echocardiographic analyses uncovered a significantly impaired systolic reserve. Mechanistically, the hallmark of the failing TG heart was an abnormal energy metabolism with decreased mitochondrial ATP, preceding the attenuated cardiac performance and leading to systolic HF. CONCLUSIONS This study shows that the VEGF-B TG accelerates metabolic maladaptation which precedes structural cardiomyopathy in experimental hypertension and ultimately leads to systolic HF.
Collapse
Affiliation(s)
- Anne-Maj Samuelsson
- Department of Biomedicine, University of Bergen, Jonas Leis vei 91, 5020 Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Jonas Leis vei 65, 5021 Bergen, Norway
| | - Theda Ulrike Patricia Bartolomaeus
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Charité platz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Potsdamer Straße 58, 10785 Berlin, Germany
| | - Harithaa Anandakumar
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Charité platz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Potsdamer Straße 58, 10785 Berlin, Germany
| | - Irene Thowsen
- Department of Biomedicine, University of Bergen, Jonas Leis vei 91, 5020 Bergen, Norway
| | - Elham Nikpey
- Department of Biomedicine, University of Bergen, Jonas Leis vei 91, 5020 Bergen, Norway
| | - Jianhua Han
- Department of Biomedicine, University of Bergen, Jonas Leis vei 91, 5020 Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Jonas Leis vei 65, 5021 Bergen, Norway
| | - Lajos Marko
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Charité platz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Potsdamer Straße 58, 10785 Berlin, Germany
| | - Kenneth Finne
- Department of Clinical Medicine, University of Bergen, Jonas Lies vei 87, 5021 Bergen, Norway
| | - Olav Tenstad
- Department of Biomedicine, University of Bergen, Jonas Leis vei 91, 5020 Bergen, Norway
| | - Johannes Eckstein
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biochemistry, Charité-University Medicine, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Nikolaus Berndt
- Deutsches Herzzentrum der Charité (DHZC), Institute of Computer-assisted Cardiovascular Medicine, Augustenburger Platz 1, 13353 Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charite Platz 1, 10117 Berlin, Germany
| | - Titus Kühne
- Deutsches Herzzentrum der Charité (DHZC), Institute of Computer-assisted Cardiovascular Medicine, Augustenburger Platz 1, 13353 Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charite Platz 1, 10117 Berlin, Germany
| | - Sarah Kedziora
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Charité platz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Potsdamer Straße 58, 10785 Berlin, Germany
| | - Ibrahim Sultan
- Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - Trude Skogstrand
- Department of Biomedicine, University of Bergen, Jonas Leis vei 91, 5020 Bergen, Norway
| | - Tine V Karlsen
- Department of Biomedicine, University of Bergen, Jonas Leis vei 91, 5020 Bergen, Norway
| | - Harri Nurmi
- Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - Sofia K Forslund
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Charité platz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Potsdamer Straße 58, 10785 Berlin, Germany
| | - Entela Bollano
- Department of Cardiology, Sahlgrenska University Hospital, Blå stråket 5, 413 45 Göteborg, Sweden
| | - Kari Alitalo
- Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - Dominik N Muller
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Charité platz 1, 10117 Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Potsdamer Straße 58, 10785 Berlin, Germany
| | - Helge Wiig
- Department of Biomedicine, University of Bergen, Jonas Leis vei 91, 5020 Bergen, Norway
| |
Collapse
|
|
48
|
Wang C, Wang X, Hu W. Molecular and cellular regulation of thermogenic fat. Front Endocrinol (Lausanne) 2023; 14:1215772. [PMID: 37465124 PMCID: PMC10351381 DOI: 10.3389/fendo.2023.1215772] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/14/2023] [Indexed: 07/20/2023] Open
Abstract
Thermogenic fat, consisting of brown and beige adipocytes, dissipates energy in the form of heat, in contrast to the characteristics of white adipocytes that store energy. Increasing energy expenditure by activating brown adipocytes or inducing beige adipocytes is a potential therapeutic strategy for treating obesity and type 2 diabetes. Thus, a better understanding of the underlying mechanisms of thermogenesis provides novel therapeutic interventions for metabolic diseases. In this review, we summarize the recent advances in the molecular regulation of thermogenesis, focusing on transcription factors, epigenetic regulators, metabolites, and non-coding RNAs. We further discuss the intercellular and inter-organ crosstalk that regulate thermogenesis, considering the heterogeneity and complex tissue microenvironment of thermogenic fat.
Collapse
Affiliation(s)
- Cuihua Wang
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangdong, China
| | - Xianju Wang
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou, China
| | - Wenxiang Hu
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
49
|
Li YQ, Xin L, Zhao YC, Li SQ, Li YN. Role of vascular endothelial growth factor B in nonalcoholic fatty liver disease and its potential value. World J Hepatol 2023; 15:786-796. [PMID: 37397934 PMCID: PMC10308292 DOI: 10.4254/wjh.v15.i6.786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/27/2023] [Accepted: 05/09/2023] [Indexed: 06/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to fatty liver disease caused by liver injury factors other than alcohol. The disease is characterized by diffuse fat infiltration, including simple steatosis (no inflammatory fat deposition), nonalcoholic fatty hepatitis, liver fibrosis, and so on, which may cause liver cirrhosis, liver failure, and even liver cancer in the later stage of disease progression. At present, the pathogenesis of NAFLD is still being studied. The "two-hit" theory, represented by lipid metabolism disorder and inflammatory reactions, is gradually enriched by the "multiple-hit" theory, which includes multiple factors, such as insulin resistance and adipocyte dysfunction. In recent years, vascular endothelial growth factor B (VEGFB) has been reported to have the potential to regulate lipid metabolism and is expected to become a novel target for ameliorating metabolic diseases, such as obesity and type 2 diabetes. This review summarizes the regulatory role of VEGFB in the onset and development of NAFLD and illustrates its underlying molecular mechanism. In conclusion, the signaling pathway mediated by VEGFB in the liver may provide an innovative approach to the diagnosis and treatment of NAFLD.
Collapse
Affiliation(s)
- Yu-Qi Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Lei Xin
- Department of Gastrointestinal Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Shang-Qi Li
- The First School of Clinical Medicine, Binzhou Medical University, Yantai 264000, Shandong, China, Yantai 264000, Shandong Province, China
| | - Ya-Nuo Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| |
Collapse
|
|
50
|
Wang S, Liu Y, Chen J, He Y, Ma W, Liu X, Sun X. Effects of multi-organ crosstalk on the physiology and pathology of adipose tissue. Front Endocrinol (Lausanne) 2023; 14:1198984. [PMID: 37383400 PMCID: PMC10293893 DOI: 10.3389/fendo.2023.1198984] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 05/26/2023] [Indexed: 06/30/2023] Open
Abstract
In previous studies, adipocytes were found to play an important role in regulating whole-body nutrition and energy balance, and are also important in energy metabolism, hormone secretion, and immune regulation. Different adipocytes have different contributions to the body, with white adipocytes primarily storing energy and brown adipocytes producing heat. Recently discovered beige adipocytes, which have characteristics in between white and brown adipocytes, also have the potential to produce heat. Adipocytes interact with other cells in the microenvironment to promote blood vessel growth and immune and neural network interactions. Adipose tissue plays an important role in obesity, metabolic syndrome, and type 2 diabetes. Dysfunction in adipose tissue endocrine and immune regulation can cause and promote the occurrence and development of related diseases. Adipose tissue can also secrete multiple cytokines, which can interact with organs; however, previous studies have not comprehensively summarized the interaction between adipose tissue and other organs. This article reviews the effect of multi-organ crosstalk on the physiology and pathology of adipose tissue, including interactions between the central nervous system, heart, liver, skeletal muscle, and intestines, as well as the mechanisms of adipose tissue in the development of various diseases and its role in disease treatment. It emphasizes the importance of a deeper understanding of these mechanisms for the prevention and treatment of related diseases. Determining these mechanisms has enormous potential for identifying new targets for treating diabetes, metabolic disorders, and cardiovascular diseases.
Collapse
Affiliation(s)
- Sufen Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yifan Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Jiaqi Chen
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yuejing He
- Clinical Laboratory, Dongguan Eighth People’s Hospital, Dongguan, China
| | - Wanrui Ma
- Department of General Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Xinguang Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Xuerong Sun
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, China
| |
Collapse
|