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Gonzalez-Nieves S, Wei X, Guignard S, Nguyen T, McQuillan J, Zhang Q, Zhang J, McGuffee RM, Ford DA, Semenkovich CF, Cifarelli V. Insulin regulates lymphatic endothelial integrity via palmitoylation. J Lipid Res 2025; 66:100775. [PMID: 40081576 PMCID: PMC12002826 DOI: 10.1016/j.jlr.2025.100775] [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: 05/02/2024] [Revised: 03/07/2025] [Accepted: 03/08/2025] [Indexed: 03/16/2025] Open
Abstract
Lipid metabolism plays a critical role in lymphatic endothelial cell (LEC) development and vessel maintenance. Altered lipid metabolism is associated with loss of lymphatic vessel integrity, which compromises organ function, protective immunity, and metabolic health. Thus, understanding how lipid metabolism affects LECs is critical for uncovering the mechanisms underlying lymphatic dysfunction. Protein palmitoylation, a lipid-based post-translational modification, has emerged as a critical regulator of protein function, stability, and interaction networks. Insulin, a master regulator of systemic lipid metabolism, also regulates protein palmitoylation. However, the role of insulin-driven palmitoylation in LEC biology remains unexplored. To examine the role of palmitoylation in LEC function, we generated the first palmitoylation proteomics profile in human LECs, validated insulin-regulated targets, and determined the role of palmitoylation in LEC barrier function. In unstimulated conditions, palmitoylation occurred primarily on proteins involved in vesicular and membrane trafficking, and in translation initiation. Insulin treatment, instead, enriched palmitoylation of proteins involved in LEC integrity, namely junctional proteins such as claudin 5, along with small GTPases and ubiquitination enzymes. We also investigated the role of the long-chain fatty acid transporter CD36, a major mediator of palmitate uptake into cells, in regulating optimal lymphatic protein palmitoylation. CD36 silencing in LECs increased by 2-fold palmitoylation of proteins involved in inflammation and immune cell activation. Overall, our findings provide novel insights into the intricate relationship between lipid modification and LEC function, suggesting that insulin and palmitoylation play a critical role in lymphatic endothelial function.
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Affiliation(s)
- Silvia Gonzalez-Nieves
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Xiaochao Wei
- Division of Endocrinology Metabolism and Lipid Research, Department of Medicine, Washington University, St. Louis, MO, USA
| | - Simon Guignard
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Thi Nguyen
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Jay McQuillan
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Qiang Zhang
- Division of Endocrinology Metabolism and Lipid Research, Department of Medicine, Washington University, St. Louis, MO, USA
| | - Jinsong Zhang
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Reagan M McGuffee
- Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - David A Ford
- Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Clay F Semenkovich
- Division of Endocrinology Metabolism and Lipid Research, Department of Medicine, Washington University, St. Louis, MO, USA; Department of Cell Biology and Physiology, Washington University, St. Louis, MO, USA
| | - Vincenza Cifarelli
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA.
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Hossain L, Gomes KP, Safarpour S, Gibson SB. The microenvironment of secondary lymphedema. The key to finding effective treatments? Biochim Biophys Acta Mol Basis Dis 2025; 1871:167677. [PMID: 39828048 DOI: 10.1016/j.bbadis.2025.167677] [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: 10/15/2024] [Revised: 01/02/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
Lymphedema is characterized by the swelling of extremities due to the accumulation of interstitial fluids. It is a painful and devastating disease that increases the risk of infections and destroys patients' quality of life. Secondary lymphedema is caused by damage to the lymphatic system due to infections, obesity, surgery, and cancer treatments. This damage fails to be repaired and leads to fluid accumulation, tissue remodeling, inflammation, and ultimately fibrosis. The lymphedema microenvironment is altered by stress, immune dysfunction, and changes in metabolism. Stress in the microenvironment includes increased hypoxia and oxidative stress but how this contributes to lymphedema progression is unclear. The immune system plays a critical role in lymphedema through T cell helper type 2 (Th2) immune responses and the infiltration of macrophages into lymphedematous tissue. The inflammatory cytokines released by immune cells lead to tissue remodeling and fibrosis. There are also changes in metabolism in the lymphedema microenvironment with altered lipid oxidation, ketone body oxidation, and glycolysis. How these changes affect lymphedema and treatment interventions has been the focus of clinical trials. Lymphedema is also associated with cancer and obesity through damage to the lymphatic system. This review will illustrate microenvironmental changes in lymphedema and how this relates to cancer and obesity. In addition, we will discuss new therapeutic strategies to treat lymphedema. Finally, we will address the prospects of lymphedema research in the context of the microenvironment.
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Affiliation(s)
- Lazina Hossain
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada
| | - Karina P Gomes
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada
| | - Samaneh Safarpour
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada
| | - Spencer B Gibson
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada.
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Seibel AJ, Frosti CL, Tlemçani AR, Lahiri N, Brammer-DePuy JA, Layne MD, Tien J. Obesity-Associated Conditions Hinder Solute Drainage Function of Engineered Human Lymphatic Vessels. Cell Mol Bioeng 2025; 18:53-69. [PMID: 39949491 PMCID: PMC11813835 DOI: 10.1007/s12195-024-00840-z] [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: 08/02/2024] [Accepted: 12/13/2024] [Indexed: 02/16/2025] Open
Abstract
Purpose Obesity is associated with poor lymphatic solute drainage. It is unclear whether the chronic inflammation, hypoxia, and hyperlipidemia that are together associated with obesity cause impaired drainage function, and if so, whether these conditions act directly on lymphatic endothelial cells (LECs) or are indirectly mediated by the mechanical properties or cellular composition of the surrounding tissue. Methods We engineered blind-ended lymphatic vessels in type I collagen gels and simulated the obese microenvironment with a cocktail of tumor necrosis factor (TNF)-α, cobalt chloride (CoCl2), and oleate, which model inflammation, hypoxia, and hyperlipidemia, respectively. We compared the solute drainage rate and leakage of lymphatics that were exposed to simulated obesity or not. We performed similar assays with lymphatics in stiffened gels, in adipocyte-laden gels, or in the presence of conditioned medium (CM) from adipose cells treated with the same cocktail. Results Lymphatics that were exposed to simulated obesity exhibited more gaps in endothelial junctions, leaked more solute, and drained solute less quickly than control lymphatics did, regardless of matrix stiffness. CM from adipose cells that were exposed to simulated obesity did not affect lymphatics. Lymphatics in adipocyte-laden gels did not exhibit worse drainage function when exposed to simulated obesity. Conclusions The combination of obesity-associated inflammation, hypoxia, and hyperlipidemia impairs lymphatic solute drainage and does so by acting directly on LECs. Surprisingly, adipocytes may play a protective role in preventing obesity-associated conditions from impairing lymphatic solute drainage. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-024-00840-z.
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Affiliation(s)
- Alex J. Seibel
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Cheyanne L. Frosti
- Department of Biochemistry & Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA USA
| | - Abderrahman R. Tlemçani
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Nikhil Lahiri
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Joely A. Brammer-DePuy
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
| | - Matthew D. Layne
- Department of Biochemistry & Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA USA
| | - Joe Tien
- Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215 USA
- Division of Materials Science and Engineering, Boston University, Boston, MA USA
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4
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Reddiar SB, Xie Y, Abdallah M, Han S, Hu L, Feeney OM, Gracia G, Anshabo A, Lu Z, Farooq MA, Styles IK, Phillips ARJ, Windsor JA, Porter CJH, Cao E, Trevaskis NL. Intestinal Lymphatic Biology, Drug Delivery, and Therapeutics: Current Status and Future Directions. Pharmacol Rev 2024; 76:1326-1398. [PMID: 39179383 DOI: 10.1124/pharmrev.123.001159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 07/29/2024] [Accepted: 08/14/2024] [Indexed: 08/26/2024] Open
Abstract
Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins, and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focused primarily on the drugs' physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic, and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs, and lipid-conjugated materials that "hitchhike" onto lymphatic transport pathways. With the increasing development of novel therapeutics such as biologics, there has been interest in whether these therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarize the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies in the future. SIGNIFICANCE STATEMENT: This comprehensive review details the understanding of the anatomy and physiology of the intestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. It highlights current state-of-the-art approaches to deliver drugs to the intestinal lymphatics and the shift toward the use of these strategies to achieve pharmacokinetic and therapeutic benefits for patients.
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Affiliation(s)
- Sanjeevini Babu Reddiar
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Yining Xie
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Mohammad Abdallah
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Sifei Han
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Luojuan Hu
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Orlagh M Feeney
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Gracia Gracia
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Abel Anshabo
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Zijun Lu
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Muhammad Asim Farooq
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Ian K Styles
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Anthony R J Phillips
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - John A Windsor
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Christopher J H Porter
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Enyuan Cao
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
| | - Natalie L Trevaskis
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (S.B.R., Y.X., M.A., S.H., L.H., O.M.F., G.G., A.A., Z.L., M.A.F., I.K.S., C.J.H.P., E.C., N.L.T.); China Pharmaceutical University, Nanjing, China (S.H., L.H.); Applied Surgery and Metabolism Laboratory, School of Biological Sciences (A.R.J.P.) and Surgical and Translational Research Centre, Department of Surgery, Faculty of Medical and Health Sciences (A.R.J.P., J.A.W.), University of Auckland, Auckland, New Zealand; and Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (N.L.T.)
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Karakousi T, Mudianto T, Lund AW. Lymphatic vessels in the age of cancer immunotherapy. Nat Rev Cancer 2024; 24:363-381. [PMID: 38605228 DOI: 10.1038/s41568-024-00681-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/27/2024] [Indexed: 04/13/2024]
Abstract
Lymphatic transport maintains homeostatic health and is necessary for immune surveillance, and yet lymphatic growth is often associated with solid tumour development and dissemination. Although tumour-associated lymphatic remodelling and growth were initially presumed to simply expand a passive route for regional metastasis, emerging research puts lymphatic vessels and their active transport at the interface of metastasis, tumour-associated inflammation and systemic immune surveillance. Here, we discuss active mechanisms through which lymphatic vessels shape their transport function to influence peripheral tissue immunity and the current understanding of how tumour-associated lymphatic vessels may both augment and disrupt antitumour immune surveillance. We end by looking forward to emerging areas of interest in the field of cancer immunotherapy in which lymphatic vessels and their transport function are likely key players: the formation of tertiary lymphoid structures, immune surveillance in the central nervous system, the microbiome, obesity and ageing. The lessons learnt support a working framework that defines the lymphatic system as a key determinant of both local and systemic inflammatory networks and thereby a crucial player in the response to cancer immunotherapy.
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Affiliation(s)
- Triantafyllia Karakousi
- Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, USA
| | - Tenny Mudianto
- Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, USA
| | - Amanda W Lund
- Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, USA.
- Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
- Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
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Engin A. Endothelial Dysfunction in Obesity and Therapeutic Targets. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:489-538. [PMID: 39287863 DOI: 10.1007/978-3-031-63657-8_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Parallel to the increasing prevalence of obesity in the world, the mortality from cardiovascular disease has also increased. Low-grade chronic inflammation in obesity disrupts vascular homeostasis, and the dysregulation of adipocyte-derived endocrine and paracrine effects contributes to endothelial dysfunction. Besides the adipose tissue inflammation, decreased nitric oxide (NO)-bioavailability, insulin resistance (IR), and oxidized low-density lipoproteins (oxLDLs) are the main factors contributing to endothelial dysfunction in obesity and the development of cardiorenal metabolic syndrome. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in the profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Higher stiffness parameter β, increased oxidative stress, upregulation of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADP) oxidase in PVAT turn the macrophages into pro-atherogenic phenotypes by oxLDL-induced adipocyte-derived exosome-macrophage crosstalk and contribute to the endothelial dysfunction. In clinical practice, carotid ultrasound, higher leptin levels correlate with irisin over-secretion by human visceral and subcutaneous adipose tissues, and remnant cholesterol (RC) levels predict atherosclerotic disease in obesity. As a novel therapeutic strategy for cardiovascular protection, liraglutide improves vascular dysfunction by modulating a cyclic adenosine monophosphate (cAMP)-independent protein kinase A (PKA)-AMP-activated protein kinase (AMPK) pathway in PVAT in obese individuals. Because the renin-angiotensin-aldosterone system (RAAS) activity, hyperinsulinemia, and the resultant IR play key roles in the progression of cardiovascular disease in obesity, RAAS-targeted therapies contribute to improving endothelial dysfunction. By contrast, arginase reciprocally inhibits NO formation and promotes oxidative stress. Thus, targeting arginase activity as a key mediator in endothelial dysfunction has therapeutic potential in obesity-related vascular comorbidities. Obesity-related endothelial dysfunction plays a pivotal role in the progression of type 2 diabetes (T2D). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (thiazolidinedione), is a popular drug for treating diabetes; however, it leads to increased cardiovascular risk. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) significantly improves endothelial dysfunction and mortality occurring through redox-dependent mechanisms. Although endothelial dysfunction and oxidative stress are alleviated by either metformin or EMPA, currently used drugs to treat obesity-related diabetes neither possess the same anti-inflammatory potential nor simultaneously target endothelial cell dysfunction and obesity equally. While therapeutic interventions with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide or bariatric surgery reverse regenerative cell exhaustion, support vascular repair mechanisms, and improve cardiometabolic risk in individuals with T2D and obesity, the GLP-1 analog exendin-4 attenuates endothelial endoplasmic reticulum stress.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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7
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Yeganeh-Hajahmadi M, Mehrabani M, Esmaili M, Farokhi MS, Sanjari M. Protamine as a barrier against the angiogenic effect of insulin: a possible role of apelin. Sci Rep 2023; 13:17267. [PMID: 37828117 PMCID: PMC10570368 DOI: 10.1038/s41598-023-44639-w] [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: 04/24/2023] [Accepted: 10/10/2023] [Indexed: 10/14/2023] Open
Abstract
Insulin is proved to have angiogenic ability thereby may worsen the diabetic retinopathy (DR) progression. Insulin also triggers the expression of endogenous angiogenic peptide, apelin. Since protamine was introduced as an inhibitor of the apelin receptor, we hypothesized that use of protaminated insulin instead of non-protaminated insulin can decrease the negative role of insulin in progression of DR. Firstly, the incidence of DR was compared among three diabetic patient groups: an oral medication, non-protaminated insulin, and protaminated insulin (PIns). Proliferation and migration rate of HUVECs was measured after insulin, apelin, and protamine exposure. In clinical study, the chance of developing DR was 8.5 and 4.1 times higher in insulin group and PIns groups compared with oral group respectively. Insulin group had a chance of 9.5-folds of non-proliferative DR compared to oral group. However, the difference of non-proliferative DR between PIns and oral group wasn't significant. In-vitro tests showed that concomitant use of insulin and apelin increases viability and migratory potential of HUVECs. However, protamine could reverse this effect. Protamine present in some insulins might show a promising protective role against diabetic retinopathy. Thus, protaminated insulins may be preferable in the treatment of diabetes.
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Affiliation(s)
- Mahboobeh Yeganeh-Hajahmadi
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mehrnaz Mehrabani
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mojdeh Esmaili
- Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Mitra Shadkam Farokhi
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Mojgan Sanjari
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Boulevard Jahad, Ebne Sina Avenue, Kerman, 76137-53767, Iran.
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8
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Breslin JW. Edema and lymphatic clearance: molecular mechanisms and ongoing challenges. Clin Sci (Lond) 2023; 137:1451-1476. [PMID: 37732545 PMCID: PMC11025659 DOI: 10.1042/cs20220314] [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: 06/03/2023] [Revised: 08/18/2023] [Accepted: 08/31/2023] [Indexed: 09/22/2023]
Abstract
Resolution of edema remains a significant clinical challenge. Conditions such as traumatic shock, sepsis, or diabetes often involve microvascular hyperpermeability, which leads to tissue and organ dysfunction. Lymphatic insufficiency due to genetic causes, surgical removal of lymph nodes, or infections, leads to varying degrees of tissue swelling that impair mobility and immune defenses. Treatment options are limited to management of edema as there are no specific therapeutics that have demonstrated significant success for ameliorating microvascular leakage or impaired lymphatic function. This review examines current knowledge about the physiological, cellular, and molecular mechanisms that control microvascular permeability and lymphatic clearance, the respective processes for interstitial fluid formation and removal. Clinical conditions featuring edema, along with potential future directions are discussed.
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Affiliation(s)
- Jerome W Breslin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, FL, U.S.A
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9
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Sawane M, Gantumur E, Muramatsu F, Kidoya H, Takakura N, Kajiya K. Apelin provides an alternative function to estrogen in regulating lymphatic vascular integrity. J Dermatol Sci 2023; 111:124-127. [PMID: 37580204 DOI: 10.1016/j.jdermsci.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 07/05/2023] [Accepted: 07/30/2023] [Indexed: 08/16/2023]
Affiliation(s)
- Mika Sawane
- Shiseido Global Innovation Center, Yokohama, Japan
| | | | - Fumitaka Muramatsu
- Department of Signal Transduction, Research Institute of Microbial Diseases, Osaka University, Suita, Japan
| | - Hiroyasu Kidoya
- Department of Signal Transduction, Research Institute of Microbial Diseases, Osaka University, Suita, Japan; Department of Integrative Vascular Biology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Nobuyuki Takakura
- Department of Signal Transduction, Research Institute of Microbial Diseases, Osaka University, Suita, Japan
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10
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The Interaction of Apelin and FGFR1 Ameliorated the Kidney Fibrosis through Suppression of TGF β-Induced Endothelial-to-Mesenchymal Transition. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:5012474. [PMID: 36785790 PMCID: PMC9922196 DOI: 10.1155/2023/5012474] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 07/11/2022] [Accepted: 09/30/2022] [Indexed: 02/06/2023]
Abstract
Both epithelial-to-mesenchymal (EMT) and endothelial-to-mesenchymal (EndMT) transitions have shown to contribute to the development and progression of kidney fibrosis. It has been reported that apelin, a regulatory peptide, alleviates EMT by inhibiting the transforming growth factor β (TGFβ) pathway in renal diseases. Additionally, fibroblast growth factor receptor 1 (FGFR1) has been shown to be a key inhibitor of EndMT through suppression of the TGFβ/Smad pathway. In this study, we found that apelin and FGFR1 were spatially close to each other and that the apelin and FGFR1 complex displayed inhibitory effects on TGFβ/Smad signaling as well as associated EndMT in diabetic kidney fibrosis. In cultured human dermal microvascular endothelial cells (HMVECs), we found that the anti-EndMT and anti-TGFβ/Smad effects of apelin were dampened in FGFR1-deficient cells. Either siRNA- or an inhibitor-mediated deficiency of apelin induced the Smad3 phosphorylation and EndMT. Streptozotocin-induced CD-1 diabetic mice displayed EndMT and associated kidney fibrosis, which were restored by apelin treatment. The medium from apelin-deficient endothelial cells stimulated TGFβ/Smad-dependent EMT in cultured HK2 cells. In addition, depletion of apelin and the FGFR1 complex impaired CEBPA expression, and TGFβ-induced repression of CEBPA expression contributed to the initiation of EndMT in the endothelium. Collectively, these findings revealed that the interaction between apelin and FGFR1 displayed renoprotective potential through suppression of the TGFβ/Smad/CEBPA-mediated EndMT/EMT pathways.
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11
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Liao ZZ, Ran L, Qi XY, Wang YD, Wang YY, Yang J, Liu JH, Xiao XH. Adipose endothelial cells mastering adipose tissues metabolic fate. Adipocyte 2022; 11:108-119. [PMID: 35067158 PMCID: PMC8786343 DOI: 10.1080/21623945.2022.2028372] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 11/16/2022] Open
Abstract
Dynamic communication within adipose tissue depends on highly vascularized structural characteristics to maintain systemic metabolic homoeostasis. Recently, it has been noted that adipose endothelial cells (AdECs) act as essential bridges for biological information transmission between adipose-resident cells. Hence, paracrine regulators that mediate crosstalk between AdECs and adipose stromal cells were summarized. We also highlight the importance of AdECs to maintain adipocytes metabolic homoeostasis by regulating insulin sensitivity, lipid turnover and plasticity. The differential regulation of AdECs in adipose plasticity often depends on vascular density and metabolic states. Although choosing pro-angiogenic or anti-angiogenic therapies for obesity is still a matter of debate in clinical settings, the growing numbers of drugs have been confirmed to play an anti-obesity effect by affecting vascularization. Pharmacologic angiogenesis intervention has great potential as therapeutic strategies for obesity.
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Affiliation(s)
- Zhe-Zhen Liao
- The First Affiliated Hospital of University of South China, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Li Ran
- The First Affiliated Hospital of University of South China, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xiao-Yan Qi
- The First Affiliated Hospital of University of South China, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Ya-Di Wang
- The First Affiliated Hospital of University of South China, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yuan-Yuan Wang
- The First Affiliated Hospital of University of South China, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jing Yang
- The First Affiliated Hospital of University of South China, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jiang-Hua Liu
- The First Affiliated Hospital of University of South China, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xin-Hua Xiao
- The First Affiliated Hospital of University of South China, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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12
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Davis MJ, Kim HJ, Nichols CG. K ATP channels in lymphatic function. Am J Physiol Cell Physiol 2022; 323:C1018-C1035. [PMID: 35785984 PMCID: PMC9550566 DOI: 10.1152/ajpcell.00137.2022] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 11/22/2022]
Abstract
KATP channels function as negative regulators of active lymphatic pumping and lymph transport. This review summarizes and critiques the evidence for the expression of specific KATP channel subunits in lymphatic smooth muscle and endothelium, the roles that they play in normal lymphatic function, and their possible involvement in multiple diseases, including metabolic syndrome, lymphedema, and Cantú syndrome. For each of these topics, suggestions are made for directions for future research.
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Affiliation(s)
- Michael J Davis
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
| | - Hae Jin Kim
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
| | - Colin G Nichols
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri
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13
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Scallan JP, Jannaway M. Lymphatic Vascular Permeability. Cold Spring Harb Perspect Med 2022; 12:a041274. [PMID: 35879102 PMCID: PMC9380735 DOI: 10.1101/cshperspect.a041274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Blood vessels have a regulated permeability to fluid and solutes, which allows for the delivery of nutrients and signaling molecules to all cells in the body, a process essential to life. The lymphatic vasculature is the second network of vessels in the body, making up part of the immune system, yet is not typically thought of as having a permeability to fluid and solute. However, the major function of the lymphatic vasculature is to regulate tissue fluid balance to prevent edema, so lymphatic vessels must be permeable to absorb and transport fluid efficiently. Only recently were lymphatic vessels discovered to be permeable, which has had many functional implications. In this review, we will provide an overview of what is known about lymphatic vascular permeability, discuss the biophysical and signaling mechanisms regulating lymphatic permeability, and examine the disease relevance of this new property of lymphatic vessels.
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Affiliation(s)
- Joshua P Scallan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA
| | - Melanie Jannaway
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA
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14
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Abstract
While most tissues exhibit their greatest growth during development, adipose tissue is capable of additional massive expansion in adults. Adipose tissue expandability is advantageous when temporarily storing fuel for use during fasting, but becomes pathological upon continuous food intake, leading to obesity and its many comorbidities. The dense vasculature of adipose tissue provides necessary oxygen and nutrients, and supports delivery of fuel to and from adipocytes under fed or fasting conditions. Moreover, the vasculature of adipose tissue comprises a major niche for multipotent progenitor cells, which give rise to new adipocytes and are necessary for tissue repair. Given the multiple, pivotal roles of the adipose tissue vasculature, impairments in angiogenic capacity may underlie obesity-associated diseases such as diabetes and cardiometabolic disease. Exciting new studies on the single-cell and single-nuclei composition of adipose tissues in mouse and humans are providing new insights into mechanisms of adipose tissue angiogenesis. Moreover, new modes of intercellular communication involving micro vesicle and exosome transfer of proteins, nucleic acids and organelles are also being recognized to play key roles. This review focuses on new insights on the cellular and signaling mechanisms underlying adipose tissue angiogenesis, and on their impact on obesity and its pathophysiological consequences.
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15
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Palmer ES, Irwin N, O’Harte FPM. Potential Therapeutic Role for Apelin and Related Peptides in Diabetes: An Update. Clin Med Insights Endocrinol Diabetes 2022; 15:11795514221074679. [PMID: 35177945 PMCID: PMC8844737 DOI: 10.1177/11795514221074679] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 01/04/2022] [Indexed: 01/10/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is an epidemic with an ever-increasing global prevalence. Current treatment strategies, although plentiful and somewhat effective, often fail to achieve desired glycaemic goals in many people, leading ultimately to disease complications. The lack of sustained efficacy of clinically-approved drugs has led to a heightened interest in the development of novel alternative efficacious antidiabetic therapies. One potential option in this regard is the peptide apelin, an adipokine that acts as an endogenous ligand of the APJ receptor. Apelin exists in various molecular isoforms and was initially studied for its cardiovascular benefits, however recent research suggests that it also plays a key role in glycaemic control. As such, apelin peptides have been shown to improve insulin sensitivity, glucose tolerance and lower circulating blood glucose. Nevertheless, native apelin has a short biological half-life that limits its therapeutic potential. More recently, analogues of apelin, particularly apelin-13, have been developed that possess a significantly extended biological half-life. These analogues may represent a promising target for future development of therapies for metabolic disease including diabetes and obesity.
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Affiliation(s)
- Ethan S Palmer
- Ethan S Palmer, Diabetes Research Group, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK.
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16
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Quantitative Methods to Assess Adipose Vasculature. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2441:201-221. [PMID: 35099739 DOI: 10.1007/978-1-0716-2059-5_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Adipose tissue depots are invested with an extensive capillary network that is closely associated with maintenance of adipose functions and enables healthy tissue expansion. The capillary network displays a high level of plasticity, demonstrating either growth (angiogenesis) or regression (rarefaction) under various physiological/pathological conditions, which has significant consequences for cardiometabolic health. Thus, the visualization and quantification of adipose vascular networks is an important aspect of studying factors that regulate adipose tissue health. This chapter provides an overview of several methods to quantify adipose vascularization. In-depth protocols are provided for the visualization of vascular structures by staining and imaging of whole-mount adipose tissues or paraffin-embedded adipose tissue sections, together with the quantitative analysis of vascularization from these images.
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17
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Davis MJ, Scallan JP, Castorena-Gonzalez JA, Kim HJ, Ying LH, Pin YK, Angeli V. Multiple aspects of lymphatic dysfunction in an ApoE -/- mouse model of hypercholesterolemia. Front Physiol 2022; 13:1098408. [PMID: 36685213 PMCID: PMC9852907 DOI: 10.3389/fphys.2022.1098408] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 12/19/2022] [Indexed: 01/07/2023] Open
Abstract
Introduction: Rodent models of cardiovascular disease have uncovered various types of lymphatic vessel dysfunction that occur in association with atherosclerosis, type II diabetes and obesity. Previously, we presented in vivo evidence for impaired lymphatic drainage in apolipoprotein E null (ApoE -/- ) mice fed a high fat diet (HFD). Whether this impairment relates to the dysfunction of collecting lymphatics remains an open question. The ApoE -/- mouse is a well-established model of cardiovascular disease, in which a diet rich in fat and cholesterol on an ApoE deficient background accelerates the development of hypercholesteremia, atherosclerotic plaques and inflammation of the skin and other tissues. Here, we investigated various aspects of lymphatic function using ex vivo tests of collecting lymphatic vessels from ApoE +/+ or ApoE -/- mice fed a HFD. Methods: Popliteal collectors were excised from either strain and studied under defined conditions in which we could quantify changes in lymphatic contractile strength, lymph pump output, secondary valve function, and collecting vessel permeability. Results: Our results show that all these aspects of lymphatic vessel function are altered in deleterious ways in this model of hypercholesterolemia. Discussion: These findings extend previous in vivo observations suggesting significant dysfunction of lymphatic endothelial cells and smooth muscle cells from collecting vessels in association with a HFD on an ApoE-deficient background. An implication of our study is that collecting vessel dysfunction in this context may negatively impact the removal of cholesterol by the lymphatic system from the skin and the arterial wall and thereby exacerbate the progression and/or severity of atherosclerosis and associated inflammation.
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Affiliation(s)
- Michael J Davis
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, United States
| | - Joshua P Scallan
- Department of Molecular Pharmacology, University of South Florida, Tampa, FL, United States
| | | | - Hae Jin Kim
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, United States
| | - Lim Hwee Ying
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
| | - Yeo Kim Pin
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore.,Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Veronique Angeli
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore.,Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
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18
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Kemp SS, Penn MR, Koller GM, Griffin CT, Davis GE. Proinflammatory mediators, TNFα, IFNγ, and thrombin, directly induce lymphatic capillary tube regression. Front Cell Dev Biol 2022; 10:937982. [PMID: 35927983 PMCID: PMC9343954 DOI: 10.3389/fcell.2022.937982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/30/2022] [Indexed: 11/30/2022] Open
Abstract
In this work, we sought to investigate the direct effects of proinflammatory mediators on lymphatic endothelial cell (LEC) capillaries and whether they might induce regression. Our laboratory has developed novel in-vitro, serum-free, lymphatic tubulogenesis assay models whereby human LEC tube networks readily form in either three-dimensional collagen or fibrin matrices. These systems were initially conceptualized in the hopes of better understanding the influence of proinflammatory mediators on LEC capillaries. In this work, we have screened and identified proinflammatory mediators that cause regression of LEC tube networks, the most potent of which is TNFα (tumor necrosis factor alpha), followed by IFNγ (interferon gamma) and thrombin. When these mediators were combined, even greater and more rapid lymphatic capillary regression occurred. Surprisingly, IL-1β (interleukin-1 beta), one of the most potent and pathologic cytokines known, had no regressive effect on these tube networks. Finally, we identified new pharmacological drug combinations capable of rescuing LEC capillaries from regression in response to the potent combination of TNFα, IFNγ, and thrombin. We speculate that protecting lymphatic capillaries from regression may be an important step toward mitigating a wide variety of acute and chronic disease states, as lymphatics are believed to clear both proinflammatory cells and mediators from inflamed and damaged tissue beds. Overall, these studies identify key proinflammatory mediators, including TNFα, IFNγ, and thrombin, that induce regression of LEC tube networks, as well as identify potential therapeutic agents to diminish LEC capillary regression responses.
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Affiliation(s)
- Scott S Kemp
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Marlena R Penn
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Gretchen M Koller
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Courtney T Griffin
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
| | - George E Davis
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
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19
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de Oliveira AA, Vergara A, Wang X, Vederas JC, Oudit GY. Apelin pathway in cardiovascular, kidney, and metabolic diseases: Therapeutic role of apelin analogs and apelin receptor agonists. Peptides 2022; 147:170697. [PMID: 34801627 DOI: 10.1016/j.peptides.2021.170697] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 02/07/2023]
Abstract
The apelin/apelin receptor (ApelinR) signal transduction pathway exerts essential biological roles, particularly in the cardiovascular system. Disturbances in the apelin/ApelinR axis are linked to vascular, heart, kidney, and metabolic disorders. Therefore, the apelinergic system has surfaced as a critical therapeutic strategy for cardiovascular diseases (including pulmonary arterial hypertension), kidney disease, insulin resistance, hyponatremia, preeclampsia, and erectile dysfunction. However, apelin peptides are susceptible to rapid degradation through endogenous peptidases, limiting their use as therapeutic tools and translational potential. These proteases include angiotensin converting enzyme 2, neutral endopeptidase, and kallikrein thereby linking the apelin pathway with other peptide systems. In this context, apelin analogs with enhanced proteolytic stability and synthetic ApelinR agonists emerged as promising pharmacological alternatives. In this review, we focus on discussing the putative roles of the apelin pathway in various physiological systems from function to dysfunction, and emphasizing the therapeutic potential of newly generated metabolically stable apelin analogs and non-peptide ApelinR agonists.
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Affiliation(s)
- Amanda A de Oliveira
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Ander Vergara
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Xiaopu Wang
- Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | - John C Vederas
- Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Gavin Y Oudit
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
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20
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Yin Y, Zhu ZX, Li Z, Chen YS, Zhu WM. Role of mesenteric component in Crohn’s disease: A friend or foe? World J Gastrointest Surg 2021; 13:1536-1549. [PMID: 35070062 PMCID: PMC8727179 DOI: 10.4240/wjgs.v13.i12.1536] [Citation(s) in RCA: 2] [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: 01/29/2021] [Revised: 08/01/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease (CD) is a complex and relapsing gastrointestinal disease with mesenteric alterations. The mesenteric neural, vascular, and endocrine systems actively take part in the gut dysbiosis-adaptive immunity-mesentery-body axis, and this axis has been proven to be bidirectional. The abnormalities of morphology and function of the mesenteric component are associated with intestinal inflammation and disease progress of CD via responses to afferent signals, neuropeptides, lymphatic drainage, adipokines, and functional cytokines. The hypertrophy of mesenteric adipose tissue plays important roles in the pathogenesis of CD by secreting large amounts of adipokines and representing a rich source of proinflammatory or profibrotic cytokines. The vascular alteration, including angiogenesis and lymphangiogenesis, is concomitant in the disease course of CD. Of note, the enlarged and obstructed lymphatic vessels, which have been described in CD patients, are likely related to the early onset submucosa edema and being a cause of CD. The function of mesenteric lymphatics is influenced by endocrine of mesenteric nerves and adipocytes. Meanwhile, the structure of the mesenteric lymphatic vessels in hypertrophic mesenteric adipose tissue is mispatterned and ruptured, which can lead to lymph leakage. Leaky lymph factors can in turn stimulate adipose tissue to proliferate and effectively elicit an immune response. The identification of the role of mesentery and the crosstalk between mesenteric tissues in intestinal inflammation may shed light on understanding the underlying mechanism of CD and help explore new therapeutic targets.
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Affiliation(s)
- Yi Yin
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhen-Xing Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhun Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Yu-Sheng Chen
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Ming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
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21
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Koch PS, Sandorski K, Heil J, Schmid CD, Kürschner SW, Hoffmann J, Winkler M, Staniczek T, de la Torre C, Sticht C, Schledzewski K, Taketo MM, Trogisch FA, Heineke J, Géraud C, Goerdt S, Olsavszky V. Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation. Front Physiol 2021; 12:722394. [PMID: 34658910 PMCID: PMC8511684 DOI: 10.3389/fphys.2021.722394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/19/2021] [Indexed: 01/20/2023] Open
Abstract
Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood–brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific Clec4g-iCre mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant Clec4g-iCretg/wt;Ctnnb1(Ex3)fl/wt (Ctnnb1OE−EC) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation (CD)34 and Apln. Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but Ctnnb1OE−EC mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As Clec4g-iCre is active in a subset of cardiac ECs, it was not unexpected that Ctnnb1OE−EC mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.
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Affiliation(s)
- Philipp-Sebastian Koch
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kajetan Sandorski
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Joschka Heil
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christian D Schmid
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sina W Kürschner
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Johannes Hoffmann
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Manuel Winkler
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Theresa Staniczek
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carolina de la Torre
- Next Generation Sequencing Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carsten Sticht
- Next Generation Sequencing Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kai Schledzewski
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Makoto Mark Taketo
- Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Felix A Trogisch
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Joerg Heineke
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Cardiovascular Physiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Cyrill Géraud
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Section of Clinical and Molecular Dermatology, Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sergij Goerdt
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Victor Olsavszky
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University and Center of Excellence in Dermatology, Mannheim, Germany.,European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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22
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Apelin-13-Mediated AMPK ameliorates endothelial barrier dysfunction in acute lung injury mice via improvement of mitochondrial function and autophagy. Int Immunopharmacol 2021; 101:108230. [PMID: 34655850 DOI: 10.1016/j.intimp.2021.108230] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/02/2021] [Accepted: 10/04/2021] [Indexed: 01/04/2023]
Abstract
Maintaining the pulmonary endothelial barrier that prevents the exudation of inflammatory factors and proteins is the key to the treatment of acute lung injury (ALI). Apelin-13 plays an important role in vascular diseases; however, the protective effects of Apelin-13 on ALI with pulmonary endothelial barrier are unknown. Therefore, mice and human umbilical vein endothelial cells (HUVECs) were injured by LPS following Apelin-13 administration. ALI mice showed reduced pulmonary vascular permeability, adhesion junction, mitochondrial function, mitochondrial biogenesis, and autophagy compared to the control group. Apelin-13 administration in ALI mice ameliorated LPS-induced lung injury, pulmonary vascular permeability, mitochondrial function, and promoted autophagic flux in mice and HUVECs. However, the effect of Apelin-13 was reduced after AMPK inhibition using Compound C. These data suggest that Apelin-13 ameliorates pulmonary vascular permeability in mice with ALI induced by LPS, which may be related to enhanced phosphorylation of AMPK to regulate mitochondrial function and autophagy.
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23
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Jannaway M, Scallan JP. VE-Cadherin and Vesicles Differentially Regulate Lymphatic Vascular Permeability to Solutes of Various Sizes. Front Physiol 2021; 12:687563. [PMID: 34621180 PMCID: PMC8491776 DOI: 10.3389/fphys.2021.687563] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/24/2021] [Indexed: 01/04/2023] Open
Abstract
Lymphatic vascular permeability prevents lymph leakage that is associated with lymphedema, lymphatic malformations, obesity, and inflammation. However, the molecular control of lymphatic permeability remains poorly understood. Recent studies have suggested that adherens junctions and vesicle transport may be involved in regulating lymphatic vessel permeability. To determine the contribution of each transport pathway, we utilized an ex vivo permeability assay to directly measure the solute flux of various molecular weight solutes across a range of pressures in intact murine collecting lymphatic vessels. Pharmacological and biological tools were used to probe the relative contributions of vesicles and junction proteins in the lymphatic vasculature. We show that the permeability of collecting lymphatic vessels is inversely related to the solute molecular weight. Further, our data reveal that vesicles selectively transport BSA, as an inhibitor of vesicle formation significantly decreased the permeability to BSA (∼60% decrease, n = 8, P = 0.02), but not to 3 kDa dextran (n = 7, P = 0.41), α-lactalbumin (n = 5, P = 0.26) or 70 kDa dextran (n = 8, P = 0.13). In contrast, disruption of VE-cadherin binding with a function blocking antibody significantly increased lymphatic vessel permeability to both 3 kDa dextran (5.7-fold increase, n = 5, P < 0.0001) and BSA (5.8-fold increase, n = 5, P < 0.0001). Thus, in the lymphatic vasculature, adherens junctions did not exhibit selectivity for any of the solutes tested here, whereas vesicles specifically transport BSA. Overall, the findings suggest that disease states that disrupt VE-cadherin localization or expression will cause significant leakage of solutes and fluid from the lymphatic vasculature.
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Affiliation(s)
- Melanie Jannaway
- Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Joshua P Scallan
- Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
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24
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Li Z, Wang S, He Y, Li Q, Gao G, Tong G. Regulation of Apelin-13 on Bcl-2 and Caspase-3 and Its Effects on Adipocyte Apoptosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:1687919. [PMID: 34603462 PMCID: PMC8486539 DOI: 10.1155/2021/1687919] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 08/30/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The effects of apelin-13 on the expression of Bcl-2 and caspase-3 factors and the apoptosis of adipocytes were studied at the cellular and animal levels. METHODS 3T3-L1 preadipocytes were cultured and grouped. The third-generation cells were added to the control DMSO solvent and amidation-modified apelin-13. The expression of Bcl-2 and caspase-3 were detected. The cell growth viability and cell apoptosis were detected. DOI model rats were established. The effects of apelin-13 on DOI rat biochemical indicators, the expression of Bcl-2, caspase-3, and cell apoptosis were investigated by injecting amidation-modified apelin-13 through the tail vein. RESULT In in vitro experiments, amidation-modified apelin-13 can significantly reduce the growth viability of adipocytes and the expression of Bcl-2, increase the expression of caspase-3, and promote the apoptosis of adipocytes. Animal experiments also show that apelin-13 modified by amidation can adjust the abnormal biochemical indicators of DOI rats, decrease the expression of Bcl-2 in adipose tissue, increase the expression of caspase-3, and promote the apoptosis of adipocytes. CONCLUSION Amidation of apelin-13 can promote fat cell apoptosis and reduce the incidence of obesity. The mechanism may be accomplished by inhibiting Bcl-2 and caspase-3 factors. This study helps us understand the effect of apelin-13 on fat cell apoptosis and hopes to provide a basis for the development of antiobesity drugs.
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Affiliation(s)
- Zhan Li
- Department of Cardiology, The First Affiliated Hospital, Changsha Medical University, Changsha 410219, Hunan Province, China
| | - Sha Wang
- Department of Endocrinology, The First Affiliated Hospital, Changsha Medical University, Changsha 410219, Hunan Province, China
| | - Yiwei He
- Department of Cardiology, The First Affiliated Hospital, Changsha Medical University, Changsha 410219, Hunan Province, China
| | - Qiong Li
- Department of Endocrinology, The First Affiliated Hospital, Changsha Medical University, Changsha 410219, Hunan Province, China
| | - Guoying Gao
- Department of Cardiology, The First Affiliated Hospital, Changsha Medical University, Changsha 410219, Hunan Province, China
| | - Guoxiang Tong
- Department of Endocrinology, The First Affiliated Hospital, Changsha Medical University, Changsha 410219, Hunan Province, China
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25
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Abstract
The endothelium acts as the barrier that prevents circulating lipids such as lipoproteins and fatty acids into the arterial wall; it also regulates normal functioning in the circulatory system by balancing vasodilation and vasoconstriction, modulating the several responses and signals. Plasma lipids can interact with endothelium via different mechanisms and produce different phenotypes. Increased plasma-free fatty acids (FFAs) levels are associated with the pathogenesis of atherosclerosis and cardiovascular diseases (CVD). Because of the multi-dimensional roles of plasma FFAs in mediating endothelial dysfunction, increased FFA level is now considered an essential link in the onset of endothelial dysfunction in CVD. FFA-mediated endothelial dysfunction involves several mechanisms, including dysregulated production of nitric oxide and cytokines, metaflammation, oxidative stress, inflammation, activation of the renin-angiotensin system, and apoptosis. Therefore, modulation of FFA-mediated pathways involved in endothelial dysfunction may prevent the complications associated with CVD risk. This review presents details as to how endothelium is affected by FFAs involving several metabolic pathways.
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26
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Cao E, Watt MJ, Nowell CJ, Quach T, Simpson JS, De Melo Ferreira V, Agarwal S, Chu H, Srivastava A, Anderson D, Gracia G, Lam A, Segal G, Hong J, Hu L, Phang KL, Escott ABJ, Windsor JA, Phillips ARJ, Creek DJ, Harvey NL, Porter CJH, Trevaskis NL. Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity. Nat Metab 2021; 3:1175-1188. [PMID: 34545251 DOI: 10.1038/s42255-021-00457-w] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 08/13/2021] [Indexed: 02/08/2023]
Abstract
Visceral adipose tissue (VAT) encases mesenteric lymphatic vessels and lymph nodes through which lymph is transported from the intestine and mesentery. Whether mesenteric lymphatics contribute to adipose tissue inflammation and metabolism and insulin resistance is unclear. Here we show that obesity is associated with profound and progressive dysfunction of the mesenteric lymphatic system in mice and humans. We find that lymph from mice and humans consuming a high-fat diet (HFD) stimulates lymphatic vessel growth, leading to the formation of highly branched mesenteric lymphatic vessels that 'leak' HFD-lymph into VAT and, thereby, promote insulin resistance. Mesenteric lymphatic dysfunction is regulated by cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF)-C-VEGF receptor (R)3 signalling. Lymph-targeted inhibition of COX-2 using a glyceride prodrug approach reverses mesenteric lymphatic dysfunction, visceral obesity and inflammation and restores glycaemic control in mice. Targeting obesity-associated mesenteric lymphatic dysfunction thus represents a potential therapeutic option to treat metabolic disease.
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Affiliation(s)
- Enyuan Cao
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
| | - Matthew J Watt
- Department of Physiology, University of Melbourne, Parkville, Victoria, Australia
| | - Cameron J Nowell
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Tim Quach
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Jamie S Simpson
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
- Puretech Health, Boston, MA, USA
| | - Vilena De Melo Ferreira
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Sonya Agarwal
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Hannah Chu
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Anubhav Srivastava
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Dovile Anderson
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Gracia Gracia
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Alina Lam
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Gabriela Segal
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
- Biological Optical Microscopy Platform, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
| | - Jiwon Hong
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
| | - Luojuan Hu
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Kian Liun Phang
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
| | - Alistair B J Escott
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
| | - John A Windsor
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
- HBP/Upper GI Unit, Department of General Surgery, Auckland City Hospital, Auckland, New Zealand
| | - Anthony R J Phillips
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
| | - Darren J Creek
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Natasha L Harvey
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Christopher J H Porter
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
| | - Natalie L Trevaskis
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
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27
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Powell DR, Revelli JP, Doree DD, DaCosta CM, Desai U, Shadoan MK, Rodriguez L, Mullens M, Yang QM, Ding ZM, Kirkpatrick LL, Vogel P, Zambrowicz B, Sands AT, Platt KA, Hansen GM, Brommage R. High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes. Diabetes Metab Syndr Obes 2021; 14:3753-3785. [PMID: 34483672 PMCID: PMC8409770 DOI: 10.2147/dmso.s322083] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/04/2021] [Indexed: 01/05/2023] Open
Abstract
PURPOSE Obesity is a major public health problem. Understanding which genes contribute to obesity may better predict individual risk and allow development of new therapies. Because obesity of a mouse gene knockout (KO) line predicts an association of the orthologous human gene with obesity, we reviewed data from the Lexicon Genome5000TM high throughput phenotypic screen (HTS) of mouse gene KOs to identify KO lines with high body fat. MATERIALS AND METHODS KO lines were generated using homologous recombination or gene trapping technologies. HTS body composition analyses were performed on adult wild-type and homozygous KO littermate mice from 3758 druggable mouse genes having a human ortholog. Body composition was measured by either DXA or QMR on chow-fed cohorts from all 3758 KO lines and was measured by QMR on independent high fat diet-fed cohorts from 2488 of these KO lines. Where possible, comparisons were made to HTS data from the International Mouse Phenotyping Consortium (IMPC). RESULTS Body fat data are presented for 75 KO lines. Of 46 KO lines where independent external published and/or IMPC KO lines are reported as obese, 43 had increased body fat. For the remaining 29 novel high body fat KO lines, Ksr2 and G2e3 are supported by data from additional independent KO cohorts, 6 (Asnsd1, Srpk2, Dpp8, Cxxc4, Tenm3 and Kiss1) are supported by data from additional internal cohorts, and the remaining 21 including Tle4, Ak5, Ntm, Tusc3, Ankk1, Mfap3l, Prok2 and Prokr2 were studied with HTS cohorts only. CONCLUSION These data support the finding of high body fat in 43 independent external published and/or IMPC KO lines. A novel obese phenotype was identified in 29 additional KO lines, with 27 still lacking the external confirmation now provided for Ksr2 and G2e3 KO mice. Undoubtedly, many mammalian obesity genes remain to be identified and characterized.
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Affiliation(s)
- David R Powell
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
| | - Jean-Pierre Revelli
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
| | - Deon D Doree
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
| | - Christopher M DaCosta
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
| | - Urvi Desai
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
| | - Melanie K Shadoan
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
| | - Lawrence Rodriguez
- Department of Information Technology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA
| | - Michael Mullens
- Department of Information Technology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA
| | - Qi M Yang
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
| | - Zhi-Ming Ding
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
| | - Laura L Kirkpatrick
- Department of Molecular Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA
| | - Peter Vogel
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
| | - Brian Zambrowicz
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
- Department of Information Technology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA
- Department of Molecular Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA
| | - Arthur T Sands
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
- Department of Information Technology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA
- Department of Molecular Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA
| | - Kenneth A Platt
- Department of Molecular Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA
| | - Gwenn M Hansen
- Department of Molecular Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, Tx, USA
| | - Robert Brommage
- Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA
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28
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Griffiths PR, Lolait SJ, Paton JFR, O'Carroll AM. Circumventricular Organ Apelin Receptor Knockdown Decreases Blood Pressure and Sympathetic Drive Responses in the Spontaneously Hypertensive Rat. Front Physiol 2021; 12:711041. [PMID: 34421653 PMCID: PMC8373520 DOI: 10.3389/fphys.2021.711041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/12/2021] [Indexed: 11/18/2022] Open
Abstract
The central site(s) mediating the cardiovascular actions of the apelin-apelin receptor (APJ) system remains a major question. We hypothesized that the sensory circumventricular organs (CVOs), interfacing between the circulation and deeper brain structures, are sites where circulating apelin acts as a signal in the central nervous system to decrease blood pressure (BP). We show that APJ gene (aplnr) expression was elevated in the CVOs of spontaneously hypertensive rats (SHRs) compared to normotensive Wistar Kyoto (WKY) controls, and that there was a greater mean arterial BP (MABP) decrease following microinjection of [Pyr1]apelin-13 to the CVOs of SHRs compared to WKY rats. Lentiviral APJ-specific-shRNA (LV-APJ-shRNA) was used to knockdown aplnr expression, both collectively in three CVOs and discretely in individual CVOs, of rats implanted with radiotelemeters to measure arterial pressure. LV-APJ-shRNA-injection decreased aplnr expression in the CVOs and abolished MABP responses to microinjection of [Pyr1]apelin-13. Chronic knockdown of aplnr in any of the CVOs, collectively or individually, did not affect basal MABP in SHR or WKY rats. Moreover, knockdown of aplnr in any of the CVOs individually did not affect the depressor response to systemic [Pyr1]apelin-13. By contrast, multiple knockdown of aplnr in the three CVOs reduced acute cardiovascular responses to peripheral [Pyr1]apelin-13 administration in SHR but not WKY rats. These results suggest that endogenous APJ activity in the CVOs has no effect on basal BP but that functional APJ in the CVOs is required for an intact cardiovascular response to peripherally administered apelin in the SHR.
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Affiliation(s)
- Philip R Griffiths
- Faculty of Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Stephen J Lolait
- Faculty of Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Julian F R Paton
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.,Faculty of Biomedical Sciences, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
| | - Anne-Marie O'Carroll
- Faculty of Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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29
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Fatty acids and evolving roles of their proteins in neurological, cardiovascular disorders and cancers. Prog Lipid Res 2021; 83:101116. [PMID: 34293403 DOI: 10.1016/j.plipres.2021.101116] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 07/04/2021] [Accepted: 07/14/2021] [Indexed: 01/03/2023]
Abstract
The dysregulation of fat metabolism is involved in various disorders, including neurodegenerative, cardiovascular, and cancers. The uptake of long-chain fatty acids (LCFAs) with 14 or more carbons plays a pivotal role in cellular metabolic homeostasis. Therefore, the uptake and metabolism of LCFAs must constantly be in tune with the cellular, metabolic, and structural requirements of cells. Many metabolic diseases are thought to be driven by the abnormal flow of fatty acids either from the dietary origin and/or released from adipose stores. Cellular uptake and intracellular trafficking of fatty acids are facilitated ubiquitously with unique combinations of fatty acid transport proteins and cytoplasmic fatty acid-binding proteins in every tissue. Extensive data are emerging on the defective transporters and metabolism of LCFAs and their clinical implications. Uptake and metabolism of LCFAs are crucial for the brain's functional development and cardiovascular health and maintenance. In addition, data suggest fatty acid metabolic transporter can normalize activated inflammatory response by reprogramming lipid metabolism in cancers. Here we review the current understanding of how LCFAs and their proteins contribute to the pathophysiology of three crucial diseases and the mechanisms involved in the processes.
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González-Loyola A, Bovay E, Kim J, Lozano TW, Sabine A, Renevey F, Arroz-Madeira S, Rapin A, Wypych TP, Rota G, Durot S, Velin D, Marsland B, Guarda G, Delorenzi M, Zamboni N, Luther SA, Petrova TV. FOXC2 controls adult lymphatic endothelial specialization, function, and gut lymphatic barrier preventing multiorgan failure. SCIENCE ADVANCES 2021; 7:eabf4335. [PMID: 34272244 PMCID: PMC8284898 DOI: 10.1126/sciadv.abf4335] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 06/01/2021] [Indexed: 05/02/2023]
Abstract
The mechanisms maintaining adult lymphatic vascular specialization throughout life and their role in coordinating inter-organ communication to sustain homeostasis remain elusive. We report that inactivation of the mechanosensitive transcription factor Foxc2 in adult lymphatic endothelium leads to a stepwise intestine-to-lung systemic failure. Foxc2 loss compromised the gut epithelial barrier, promoted dysbiosis and bacterial translocation to peripheral lymph nodes, and increased circulating levels of purine metabolites and angiopoietin-2. Commensal microbiota depletion dampened systemic pro-inflammatory cytokine levels, corrected intestinal lymphatic dysfunction, and improved survival. Foxc2 loss skewed the specialization of lymphatic endothelial subsets, leading to populations with mixed, pro-fibrotic identities and to emergence of lymph node-like endothelial cells. Our study uncovers a cross-talk between lymphatic vascular function and commensal microbiota, provides single-cell atlas of lymphatic endothelial subtypes, and reveals organ-specific and systemic effects of dysfunctional lymphatics. These effects potentially contribute to the pathogenesis of diseases, such as inflammatory bowel disease, cancer, or lymphedema.
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Affiliation(s)
- Alejandra González-Loyola
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Epalinges 1066, Switzerland
| | - Esther Bovay
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Epalinges 1066, Switzerland
| | - Jaeryung Kim
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Epalinges 1066, Switzerland
| | - Tania Wyss Lozano
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Epalinges 1066, Switzerland
- SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland
| | - Amélie Sabine
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Epalinges 1066, Switzerland
| | - Francois Renevey
- Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland
| | - Silvia Arroz-Madeira
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Epalinges 1066, Switzerland
| | - Alexis Rapin
- École Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland
| | - Tomasz P Wypych
- Department of Immunology and Pathology, Monash University, Melbourne 3800, Australia
| | - Giorgia Rota
- Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland
| | - Stephan Durot
- Institute of Molecular Systems Biology ETH, Zurich 8093, Switzerland
| | - Dominique Velin
- Service of Gastroenterology and Hepatology, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland
| | - Benjamin Marsland
- Department of Immunology and Pathology, Monash University, Melbourne 3800, Australia
| | - Greta Guarda
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Bellinzona, Switzerland
| | - Mauro Delorenzi
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Epalinges 1066, Switzerland
- SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland
| | - Nicola Zamboni
- Institute of Molecular Systems Biology ETH, Zurich 8093, Switzerland
| | - Sanjiv A Luther
- Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland
| | - Tatiana V Petrova
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Epalinges 1066, Switzerland.
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Morfoisse F, De Toni F, Nigri J, Hosseini M, Zamora A, Tatin F, Pujol F, Sarry JE, Langin D, Lacazette E, Prats AC, Tomasini R, Galitzky J, Bouloumié A, Garmy-Susini B. Coordinating Effect of VEGFC and Oleic Acid Participates to Tumor Lymphangiogenesis. Cancers (Basel) 2021; 13:cancers13122851. [PMID: 34200994 PMCID: PMC8227717 DOI: 10.3390/cancers13122851] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/18/2021] [Accepted: 05/25/2021] [Indexed: 01/22/2023] Open
Abstract
Simple Summary In cancer, the lymphatic system is hijacked by tumor cells that escape from primary tumor and metastasize to the sentinel lymph nodes. Tumor lymphangiogenesis is stimulated by the vascular endothelial growth factors-C (VEGFC) after binding to its receptor VEGFR-3. However, how VEGFC cooperates with other molecules to promote lymphatic neovessel growth has not been fully determined. Here, we showed that tumor lymphangiogenesis developed in tumoral lesions and in their surrounding adipose tissue (AT). Interestingly, lymphatic vessel density correlated with an increase in circulating free fatty acids (FFA) in the lymph from tumor-bearing mice. We showed that adipocyte-released FFA are uploaded by lymphatic endothelial cells (LEC) to stimulate their sprouting. Lipidomic analysis identified the monounsaturated oleic acid (OA) as the major circulating FFA in the lymph in a tumoral context. OA transporters FATP-3, -6 and CD36 were only upregulated on LEC in the presence of VEGFC showing a collaborative effect of these molecules. OA released from adipocytes is taken up by LECs to stimulate the fatty acid β-oxidation, leading to increased adipose tissue lymphangiogenesis. Our results provide new insights on the dialogue between tumors and adipocytes via the lymphatic system and identify a key role for adipocyte-derived FFA in the promotion of lymphangiogenesis, revealing novel therapeutic opportunities for inhibitors of lymphangiogenesis in cancer. Abstract In cancer, the lymphatic system is hijacked by tumor cells that escape from primary tumor and metastasize to the sentinel lymph nodes. Tumor lymphangiogenesis is stimulated by the vascular endothelial growth factors-C (VEGFC) after binding to its receptor VEGFR-3. However, how VEGFC cooperates with other molecules to promote lymphatics growth has not been fully determined. We showed that lymphangiogenesis developed in tumoral lesions and in surrounding adipose tissue (AT). Interestingly, lymphatic vessel density correlated with an increase in circulating free fatty acids (FFA) in the lymph from tumor-bearing mice. We showed that adipocyte-released FFA are uploaded by lymphatic endothelial cells (LEC) to stimulate their sprouting. Lipidomic analysis identified the monounsaturated oleic acid (OA) as the major circulating FFA in the lymph in a tumoral context. OA transporters FATP-3, -6 and CD36 were only upregulated on LEC in the presence of VEGFC showing a collaborative effect of these molecules. OA stimulates fatty acid β-oxidation in LECs, leading to increased AT lymphangiogenesis. Our results provide new insights on the dialogue between tumors and adipocytes via the lymphatic system and identify a key role for adipocyte-derived FFA in the promotion of lymphangiogenesis, revealing novel therapeutic opportunities for inhibitors of lymphangiogenesis in cancer.
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Affiliation(s)
- Florent Morfoisse
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
| | - Fabienne De Toni
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
| | - Jeremy Nigri
- CRCM, Inserm UMR 1068, 13001 Marseille, France; (J.N.); (R.T.)
| | - Mohsen Hosseini
- CRCT, Université de Toulouse, Inserm UMR 1037, UPS, 31000 Toulouse, France; (M.H.); (J.-E.S.)
| | - Audrey Zamora
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
| | - Florence Tatin
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
| | - Françoise Pujol
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
| | - Jean-Emmanuel Sarry
- CRCT, Université de Toulouse, Inserm UMR 1037, UPS, 31000 Toulouse, France; (M.H.); (J.-E.S.)
| | - Dominique Langin
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
| | - Eric Lacazette
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
| | - Anne-Catherine Prats
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
| | | | - Jean Galitzky
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
| | - Anne Bouloumié
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
| | - Barbara Garmy-Susini
- I2MC, Université de Toulouse, Inserm UMR 1297, UPS, 31000 Toulouse, France; (F.M.); (F.D.T.); (A.Z.); (F.T.); (F.P.); (D.L.); (E.L.); (A.-C.P.); (J.G.); (A.B.)
- Correspondence:
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Cifarelli V, Appak-Baskoy S, Peche VS, Kluzak A, Shew T, Narendran R, Pietka KM, Cella M, Walls CW, Czepielewski R, Ivanov S, Randolph GJ, Augustin HG, Abumrad NA. Visceral obesity and insulin resistance associate with CD36 deletion in lymphatic endothelial cells. Nat Commun 2021; 12:3350. [PMID: 34099721 PMCID: PMC8184948 DOI: 10.1038/s41467-021-23808-3] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 05/13/2021] [Indexed: 12/18/2022] Open
Abstract
Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36ΔLEC) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36ΔLEC mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D. Genetic variants in CD36 have been associated with metabolic syndrome. Here, the authors found that lymphatic vessel integrity and lipid transport are influenced by CD36 expression, and lymphatic endothelial cell CD36 deficiency causes visceral obesity and insulin resistance, which are risk factors for metabolic syndrome and diabetes.
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Affiliation(s)
- Vincenza Cifarelli
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, USA.
| | - Sila Appak-Baskoy
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.,Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Vivek S Peche
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, USA
| | - Andrew Kluzak
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, USA
| | - Trevor Shew
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, USA
| | - Ramkumar Narendran
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, USA
| | - Kathryn M Pietka
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, USA
| | - Marina Cella
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA
| | - Curtis W Walls
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, USA
| | - Rafael Czepielewski
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA
| | - Stoyan Ivanov
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA
| | - Gwendalyn J Randolph
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA
| | - Hellmut G Augustin
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.,Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Nada A Abumrad
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, USA. .,Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, USA.
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Castan-Laurell I, Dray C, Valet P. The therapeutic potentials of apelin in obesity-associated diseases. Mol Cell Endocrinol 2021; 529:111278. [PMID: 33838166 DOI: 10.1016/j.mce.2021.111278] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/26/2021] [Accepted: 04/02/2021] [Indexed: 01/23/2023]
Abstract
Apelin, a peptide with several active isoforms ranging from 36 to 12 amino acids and its receptor APJ, a G-protein-coupled receptor, are widely distributed. However, apelin has emerged as an adipokine more than fifteen years ago, integrating the field of inter-organs interactions. The apelin/APJ system plays important roles in several physiological functions both in rodent and humans such as fluid homeostasis, cardiovascular physiology, angiogenesis, energy metabolism. Thus the apelin/APJ system has generated great interest as a potential therapeutic target in different pathologies. The present review will consider the effects of apelin in metabolic diseases such as obesity and diabetes with a focus on diabetic cardiomyopathy among the complications associated with diabetes and APJ agonists or antagonists of interest in these diseases.
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Affiliation(s)
- I Castan-Laurell
- Restore UMR1301 Inserm, 5070 CNRS, Université Paul Sabatier, France.
| | - C Dray
- Restore UMR1301 Inserm, 5070 CNRS, Université Paul Sabatier, France
| | - P Valet
- Restore UMR1301 Inserm, 5070 CNRS, Université Paul Sabatier, France
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Koc M, Wald M, Varaliová Z, Ondrůjová B, Čížková T, Brychta M, Kračmerová J, Beranová L, Pala J, Šrámková V, Šiklová M, Gojda J, Rossmeislová L. Lymphedema alters lipolytic, lipogenic, immune and angiogenic properties of adipose tissue: a hypothesis-generating study in breast cancer survivors. Sci Rep 2021; 11:8171. [PMID: 33854130 PMCID: PMC8046998 DOI: 10.1038/s41598-021-87494-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 03/30/2021] [Indexed: 12/26/2022] Open
Abstract
Later stages of secondary lymphedema are associated with the massive deposition of adipose tissue (AT). The factors driving lymphedema-associated AT (LAT) expansion in humans remain rather elusive. We hypothesized that LAT expansion could be based on alterations of metabolic, adipogenic, immune and/or angiogenic qualities of AT. AT samples were acquired from upper limbs of 11 women with unilateral breast cancer-related lymphedema and 11 healthy women without lymphedema. Additional control group of 11 female breast cancer survivors without lymphedema was used to assess systemic effects of lymphedema. AT was analysed for adipocyte size, lipolysis, angiogenesis, secretion of cytokines, immune and stem cell content and mRNA gene expression. Further, adipose precursors were isolated and tested for their proliferative and adipogenic capacity. The effect of undrained LAT- derived fluid on adipogenesis was also examined. Lymphedema did not have apparent systemic effect on metabolism and cytokine levels, but it was linked with higher lymphocyte numbers and altered levels of several miRNAs in blood. LAT showed higher basal lipolysis, (lymph)angiogenic capacity and secretion of inflammatory cytokines when compared to healthy AT. LAT contained more activated CD4+ T lymphocytes than healthy AT. mRNA levels of (lymph)angiogenic markers were deregulated in LAT and correlated with markers of lipolysis. In vitro, adipose cells derived from LAT did not differ in their proliferative, adipogenic, lipogenic and lipolytic potential from cells derived from healthy AT. Nevertheless, exposition of preadipocytes to LAT-derived fluid improved their adipogenic conversion when compared with the effect of serum. This study presents results of first complex analysis of LAT from upper limb of breast cancer survivors. Identified LAT alterations indicate a possible link between (lymph)angiogenesis and lipolysis. In addition, our in vitro results imply that AT expansion in lymphedema could be driven partially by exposition of adipose precursors to undrained LAT-derived fluid.
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Affiliation(s)
- Michal Koc
- Department of Pathophysiology, Centre for Research On Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic
| | - Martin Wald
- Department of Surgery, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague 5, Czech Republic
| | - Zuzana Varaliová
- Department of Pathophysiology, Centre for Research On Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic
| | - Barbora Ondrůjová
- Department of Pathophysiology, Centre for Research On Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic
| | - Terezie Čížková
- Department of Pathophysiology, Centre for Research On Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic
| | - Milan Brychta
- Department of Radiotherapy and Oncology, Kralovske Vinohrady University Hospital, Prague 10, Czech Republic
| | - Jana Kračmerová
- Department of Pathophysiology, Centre for Research On Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic
| | - Lenka Beranová
- Department of Pathophysiology, Centre for Research On Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic
| | - Jan Pala
- Department of Pathophysiology, Centre for Research On Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic
| | - Veronika Šrámková
- Department of Pathophysiology, Centre for Research On Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic.,Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague 10, Czech Republic
| | - Michaela Šiklová
- Department of Pathophysiology, Centre for Research On Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic.,Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague 10, Czech Republic
| | - Jan Gojda
- Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague 10, Czech Republic.,Second Internal Medicine Department, Kralovske Vinohrady University Hospital, Prague 10, Czech Republic
| | - Lenka Rossmeislová
- Department of Pathophysiology, Centre for Research On Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic. .,Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague 10, Czech Republic.
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Interaction between the apelinergic system and ACE2 in the cardiovascular system: therapeutic implications. Clin Sci (Lond) 2021; 134:2319-2336. [PMID: 32901821 DOI: 10.1042/cs20200479] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/27/2020] [Accepted: 09/01/2020] [Indexed: 12/13/2022]
Abstract
The apelinergic system is widely expressed and acts through autocrine and paracrine signaling to exert protective effects, including vasodilatory, metabolic, and inotropic effects on the cardiovascular (CV) system. The apelin pathway's dominant physiological role has delineated therapeutic implications for coronary artery disease, heart failure (HF), aortic aneurysm, pulmonary arterial hypertension (PAH), and transplant vasculopathy. Apelin peptides interact with the renin-angiotensin system (RAS) by promoting angiotensin converting enzyme 2 (ACE2) transcription leading to increased ACE2 protein and activity while also antagonizing the effects of angiotensin II (Ang II). Apelin modulation of the RAS by increasing ACE2 action is limited due to its rapid degradation by proteases, including ACE2, neprilysin (NEP), and kallikrein. Apelin peptides are hence tightly regulated in a negative feedback manner by ACE2. Plasma apelin levels are suppressed in pathological conditions, but its diagnostic and prognostic utility requires further clinical exploration. Enhancing the beneficial actions of apelin peptides and ACE2 axes while complementing existing pharmacological blockade of detrimental pathways is an exciting pathway for developing new therapies. In this review, we highlight the interaction between the apelin and ACE2 systems, discuss their pathophysiological roles and potential for treating a wide array of CV diseases (CVDs).
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36
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Narayanan S, Wang S, Vasukuttan V, Vyas Devambatla RK, Dai D, Jin C, Snyder R, Laudermilk L, Runyon SP, Maitra R. Pyrazole Agonist of the Apelin Receptor Improves Symptoms of Metabolic Syndrome in Mice. J Med Chem 2021; 64:3006-3025. [PMID: 33705126 DOI: 10.1021/acs.jmedchem.0c01448] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Apelin receptor agonism improves symptoms of metabolic syndrome. However, endogenous apelin peptides have short half-lives, making their utility as potential drugs limited. Previously, we had identified a novel pyrazole-based agonist scaffold. Systematic modification of this scaffold was performed to produce compounds with improved ADME properties. Compound 13 with favorable agonist potency (cAMPi EC50 = 162 nM), human liver microsome stability (T1/2 = 62 min), and pharmacokinetic profile in rodents was identified. The compound was tested in a mouse model of diet-induced obesity (DIO) and metabolic syndrome for efficacy. Treatment with 13 led to significant weight loss, hypophagia, improved glucose utilization, reduced liver steatosis, and improvement of disease-associated biomarkers. In conclusion, a small-molecule agonist of the apelin receptor has been identified that is suitable for in vivo investigation of the apelinergic system in DIO and perhaps other diseases where this receptor has been implicated to play a role.
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Affiliation(s)
- Sanju Narayanan
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina 27709, United States
| | - Shaobin Wang
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina 27709, United States
| | - Vineetha Vasukuttan
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina 27709, United States
| | | | - Donghua Dai
- Sterling Pharma Solutions Limited, Sheldon Drive, Cary, North Carolina 27513, United States
| | - Chunyang Jin
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina 27709, United States
| | - Rodney Snyder
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina 27709, United States
| | - Lucas Laudermilk
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina 27709, United States
| | - Scott P Runyon
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina 27709, United States
| | - Rangan Maitra
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina 27709, United States
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Feng X, Travisano S, Pearson CA, Lien CL, Harrison MRM. The Lymphatic System in Zebrafish Heart Development, Regeneration and Disease Modeling. J Cardiovasc Dev Dis 2021; 8:21. [PMID: 33669620 PMCID: PMC7922492 DOI: 10.3390/jcdd8020021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 01/18/2023] Open
Abstract
Heart disease remains the single largest cause of death in developed countries, and novel therapeutic interventions are desperately needed to alleviate this growing burden. The cardiac lymphatic system is the long-overlooked counterpart of the coronary blood vasculature, but its important roles in homeostasis and disease are becoming increasingly apparent. Recently, the cardiac lymphatic vasculature in zebrafish has been described and its role in supporting the potent regenerative response of zebrafish heart tissue investigated. In this review, we discuss these findings in the wider context of lymphatic development, evolution and the promise of this system to open new therapeutic avenues to treat myocardial infarction and other cardiopathologies.
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Affiliation(s)
- Xidi Feng
- The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (X.F.); (S.T.)
| | - Stanislao Travisano
- The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (X.F.); (S.T.)
| | - Caroline A. Pearson
- Laboratory of Neurogenetics and Development, Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10021, USA;
| | - Ching-Ling Lien
- The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (X.F.); (S.T.)
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Michael R. M. Harrison
- Cardiovascular Research Institute, Weill Cornell Medical College, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10021, USA
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Estienne A, Bongrani A, Froment P, Dupont J. Apelin and chemerin receptors are G protein-coupled receptors involved in metabolic as well as reproductive functions: Potential therapeutic implications? ACTA ACUST UNITED AC 2021. [DOI: 10.1016/j.coemr.2020.09.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Capillary Rarefaction in Obesity and Metabolic Diseases-Organ-Specificity and Possible Mechanisms. Cells 2020; 9:cells9122683. [PMID: 33327460 PMCID: PMC7764934 DOI: 10.3390/cells9122683] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/02/2020] [Accepted: 12/10/2020] [Indexed: 12/11/2022] Open
Abstract
Obesity and its comorbidities like diabetes, hypertension and other cardiovascular disorders are the leading causes of death and disability worldwide. Metabolic diseases cause vascular dysfunction and loss of capillaries termed capillary rarefaction. Interestingly, obesity seems to affect capillary beds in an organ-specific manner, causing morphological and functional changes in some tissues but not in others. Accordingly, treatment strategies targeting capillary rarefaction result in distinct outcomes depending on the organ. In recent years, organ-specific vasculature and endothelial heterogeneity have been in the spotlight in the field of vascular biology since specialized vascular systems have been shown to contribute to organ function by secreting varying autocrine and paracrine factors and by providing niches for stem cells. This review summarizes the recent literature covering studies on organ-specific capillary rarefaction observed in obesity and metabolic diseases and explores the underlying mechanisms, with multiple modes of action proposed. It also provides a glimpse of the reported therapeutic perspectives targeting capillary rarefaction. Further studies should address the reasons for such organ-specificity of capillary rarefaction, investigate strategies for its prevention and reversibility and examine potential signaling pathways that can be exploited to target it.
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40
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Dupont G, Bordes SJ, Lachkar S, Wahl L, Iwanaga J, Loukas M, Tubbs RS. The effects of obesity on the human body part II: Nervous, respiratory, and lymphatic systems. Clin Anat 2020; 34:303-306. [PMID: 33048388 DOI: 10.1002/ca.23695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/08/2020] [Indexed: 11/10/2022]
Abstract
This second installment of The Effects of Obesity on the Human Body considers the nervous, respiratory, and lymphatic systems. Those with obesity face countless psychological hurdles in addition to the respiratory burden and widespread inflammation that can suppress the immune system, resulting in the accumulation of excess fluid in body tissues.
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Affiliation(s)
- Graham Dupont
- Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Stephen J Bordes
- Department of Anatomical Sciences, St. George's University School of Medicine, St. George's, Grenada
| | | | - Lauren Wahl
- Department of Cell and Developmental Biology, University of Colorado, Boulder, Colorado, USA
| | - Joe Iwanaga
- Division of Gross and Clinical Anatomy, Department of Anatomy, Kurume University School of Medicine, Kurume, Fukuoka, Japan.,Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, New Orleans, Louisiana, USA.,Department of Neurology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Marios Loukas
- Department of Anatomical Sciences, St. George's University School of Medicine, St. George's, Grenada.,Department of Anatomy, University of Warmia and Mazury, Olsztyn, Poland
| | - R Shane Tubbs
- Department of Anatomical Sciences, St. George's University School of Medicine, St. George's, Grenada.,Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, New Orleans, Louisiana, USA.,Department of Neurology, Tulane University School of Medicine, New Orleans, Louisiana, USA.,Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA
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41
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Suriyaprom K, Pheungruang B, Tungtrongchitr R, Sroijit OUY. Relationships of apelin concentration and APLN T-1860C polymorphism with obesity in Thai children. BMC Pediatr 2020; 20:455. [PMID: 32998691 PMCID: PMC7526109 DOI: 10.1186/s12887-020-02350-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 09/15/2020] [Indexed: 01/22/2023] Open
Abstract
Background Childhood obesity represents a serious global health crisis. Apelin and its receptor system are widely distributed throughout the central nervous system and have been demonstrated to serve a role modulating feeding behaviour and energy homeostasis. The purposes of this study were to examine apelin concentrations and anthropometric-cardiometabolic parameters in obese and non-obese children and to identify associations of APLN T-1860C and APLNR G212A polymorphisms with apelin levels and obesity among Thai children. Methods This case-control study included an analysis of 325 Thai children: 198 children with obesity and 127 healthy non-obese children. Anthropometric-cardiometabolic variables and apelin concentration were measured. Genotyping of APLN T-1860C and APLNR G212A was performed using the polymerase chain reaction-restriction fragment length polymorphism technique. Results The obese group had significantly lower apelin and HDL-C levels but significantly higher triglycerides and glucose (TyG) index values, TG/HDL-C ratio and TC/HDL-C ratio than the non-obese group (p < 0.01). Apelin level was negatively correlated with body size phenotypes and cardiometabolic parameters (p < 0.05). The APLN T-1860C polymorphism (OR = 4.39, 95% CI = 1.25–15.28) and apelin concentration (OR = 0.45, 95% CI = 0.23–0.92) were significantly associated with obesity among female children (p < 0.05) only, after adjusting for potential covariates. However, the APLNR G212A polymorphism showed no significant relationship with apelin concentration or obesity. Conclusion These findings in Thai children suggest that apelin concentrations are related to obesity and cardiometabolic parameters. Furthermore, the APLN T-1860C polymorphism may influence susceptibility to obesity among female children.
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Affiliation(s)
- Kanjana Suriyaprom
- Faculty of Medical Technology, Rangsit University, Paholyothin Road, Mueang Pathum Thani district, Pathum Thani, 12000, Thailand.
| | - Banchamaphon Pheungruang
- Department of Tropical Nutrition & Food Science, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Rajthevee, Bangkok, 10400, Thailand
| | - Rungsunn Tungtrongchitr
- Department of Tropical Nutrition & Food Science, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Rajthevee, Bangkok, 10400, Thailand
| | - Orn-Uma Y Sroijit
- Faculty of Medical Technology, Rangsit University, Paholyothin Road, Mueang Pathum Thani district, Pathum Thani, 12000, Thailand
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42
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Helker CS, Eberlein J, Wilhelm K, Sugino T, Malchow J, Schuermann A, Baumeister S, Kwon HB, Maischein HM, Potente M, Herzog W, Stainier DY. Apelin signaling drives vascular endothelial cells toward a pro-angiogenic state. eLife 2020; 9:55589. [PMID: 32955436 PMCID: PMC7567607 DOI: 10.7554/elife.55589] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 09/19/2020] [Indexed: 12/18/2022] Open
Abstract
To form new blood vessels (angiogenesis), endothelial cells (ECs) must be activated and acquire highly migratory and proliferative phenotypes. However, the molecular mechanisms that govern these processes are incompletely understood. Here, we show that Apelin signaling functions to drive ECs into such an angiogenic state. Zebrafish lacking Apelin signaling exhibit defects in endothelial tip cell morphology and sprouting. Using transplantation experiments, we find that in mosaic vessels, wild-type ECs leave the dorsal aorta (DA) and form new vessels while neighboring ECs defective in Apelin signaling remain in the DA. Mechanistically, Apelin signaling enhances glycolytic activity in ECs at least in part by increasing levels of the growth-promoting transcription factor c-Myc. Moreover, APELIN expression is regulated by Notch signaling in human ECs, and its function is required for the hypersprouting phenotype in Delta-like 4 (Dll4) knockdown zebrafish embryos. These data provide new insights into fundamental principles of blood vessel formation and Apelin signaling, enabling a better understanding of vascular growth in health and disease.
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Affiliation(s)
- Christian Sm Helker
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,Philipps-University Marburg, Faculty of Biology, Cell Signaling and Dynamics, Marburg, Germany
| | - Jean Eberlein
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,Philipps-University Marburg, Faculty of Biology, Cell Signaling and Dynamics, Marburg, Germany
| | - Kerstin Wilhelm
- Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Toshiya Sugino
- Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Julian Malchow
- Philipps-University Marburg, Faculty of Biology, Cell Signaling and Dynamics, Marburg, Germany
| | | | - Stefan Baumeister
- Philipps-University Marburg, Faculty of Biology, Cell Signaling and Dynamics, Marburg, Germany
| | - Hyouk-Bum Kwon
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Hans-Martin Maischein
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Michael Potente
- Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,DZHK (German Center for Cardiovascular Research), partner site Frankfurt Rhine-Main, Berlin, Germany
| | - Wiebke Herzog
- University of Muenster, Muenster, Germany.,Max Planck Institute for Molecular Biomedicine, Muenster, Germany
| | - Didier Yr Stainier
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,DZHK (German Center for Cardiovascular Research), partner site Frankfurt Rhine-Main, Berlin, Germany
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43
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Oliver G, Kipnis J, Randolph GJ, Harvey NL. The Lymphatic Vasculature in the 21 st Century: Novel Functional Roles in Homeostasis and Disease. Cell 2020; 182:270-296. [PMID: 32707093 PMCID: PMC7392116 DOI: 10.1016/j.cell.2020.06.039] [Citation(s) in RCA: 420] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/17/2020] [Accepted: 06/25/2020] [Indexed: 12/19/2022]
Abstract
Mammals have two specialized vascular circulatory systems: the blood vasculature and the lymphatic vasculature. The lymphatic vasculature is a unidirectional conduit that returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays major roles in immune cell trafficking and lipid absorption. As we discuss in this review, the molecular characterization of lymphatic vascular development and our understanding of this vasculature's role in pathophysiological conditions has greatly improved in recent years, changing conventional views about the roles of the lymphatic vasculature in health and disease. Morphological or functional defects in the lymphatic vasculature have now been uncovered in several pathological conditions. We propose that subtle asymptomatic alterations in lymphatic vascular function could underlie the variability seen in the body's response to a wide range of human diseases.
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Affiliation(s)
- Guillermo Oliver
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
| | - Jonathan Kipnis
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA
| | - Gwendalyn J Randolph
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Natasha L Harvey
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
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44
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Bardanzellu F, Puddu M, Fanos V. The Human Breast Milk Metabolome in Preeclampsia, Gestational Diabetes, and Intrauterine Growth Restriction: Implications for Child Growth and Development. J Pediatr 2020; 221S:S20-S28. [PMID: 32482230 DOI: 10.1016/j.jpeds.2020.01.049] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 01/16/2020] [Accepted: 01/21/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Flaminia Bardanzellu
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU University of Cagliari, Italy.
| | - Melania Puddu
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU University of Cagliari, Italy
| | - Vassilios Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU University of Cagliari, Italy
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45
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Gancz D, Perlmoter G, Yaniv K. Formation and Growth of Cardiac Lymphatics during Embryonic Development, Heart Regeneration, and Disease. Cold Spring Harb Perspect Biol 2020; 12:cshperspect.a037176. [PMID: 31818858 DOI: 10.1101/cshperspect.a037176] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The lymphatic system plays crucial roles in regulating fluid homeostasis, immune surveillance, and lipid transport. As is in most of the body's organs, the heart possesses an extensive lymphatic network. Moreover, a robust lymphangiogenic response has been shown to take place following myocardial infarction, highlighting cardiac lymphatics as potential targets for therapeutic intervention. Yet, the unique molecular properties and functions of the heart's lymphatic system have only recently begun to be addressed. In this review, we discuss the mechanisms underlying the formation and growth of cardiac lymphatics during embryonic development and describe their characteristics across species. We further summarize recent findings highlighting diverse cellular origins for cardiac lymphatic endothelial cells and how they integrate to form a single functional lymphatic network. Finally, we outline novel therapeutic avenues aimed at enhancing lymphatic vessel formation and integrity following cardiac injury, which hold great promise for promoting healing of the infarcted heart.
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Affiliation(s)
- Dana Gancz
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Gal Perlmoter
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Karina Yaniv
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
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46
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Zhang F, Zarkada G, Yi S, Eichmann A. Lymphatic Endothelial Cell Junctions: Molecular Regulation in Physiology and Diseases. Front Physiol 2020; 11:509. [PMID: 32547411 PMCID: PMC7274196 DOI: 10.3389/fphys.2020.00509] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 04/27/2020] [Indexed: 12/13/2022] Open
Abstract
Lymphatic endothelial cells (LECs) lining lymphatic vessels develop specialized cell-cell junctions that are crucial for the maintenance of vessel integrity and proper lymphatic vascular functions. Successful lymphatic drainage requires a division of labor between lymphatic capillaries that take up lymph via open "button-like" junctions, and collectors that transport lymph to veins, which have tight "zipper-like" junctions that prevent lymph leakage. In recent years, progress has been made in the understanding of these specialized junctions, as a result of the application of state-of-the-art imaging tools and novel transgenic animal models. In this review, we discuss lymphatic development and mechanisms governing junction remodeling between button and zipper-like states in LECs. Understanding lymphatic junction remodeling is important in order to unravel lymphatic drainage regulation in obesity and inflammatory diseases and may pave the way towards future novel therapeutic interventions.
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Affiliation(s)
- Feng Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Georgia Zarkada
- Department of Cellular and Molecular Physiology, Cardiovascular Research Center, Yale School of Medicine, Yale University, New Haven, CT, United States
| | - Sanjun Yi
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Anne Eichmann
- Department of Cellular and Molecular Physiology, Cardiovascular Research Center, Yale School of Medicine, Yale University, New Haven, CT, United States.,INSERM U970, Paris Cardiovascular Research Center, Paris, France
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47
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Kataru RP, Park HJ, Baik JE, Li C, Shin J, Mehrara BJ. Regulation of Lymphatic Function in Obesity. Front Physiol 2020; 11:459. [PMID: 32499718 PMCID: PMC7242657 DOI: 10.3389/fphys.2020.00459] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/16/2020] [Indexed: 12/15/2022] Open
Abstract
The lymphatic system has many functions, including macromolecules transport, fat absorption, regulation and modulation of adaptive immune responses, clearance of inflammatory cytokines, and cholesterol metabolism. Thus, it is evident that lymphatic function can play a key role in the regulation of a wide array of biologic phenomenon, and that physiologic changes that alter lymphatic function may have profound pathologic effects. Recent studies have shown that obesity can markedly impair lymphatic function. Obesity-induced pathologic changes in the lymphatic system result, at least in part, from the accumulation of inflammatory cells around lymphatic vessel leading to impaired lymphatic collecting vessel pumping capacity, leaky initial and collecting lymphatics, alterations in lymphatic endothelial cell (LEC) gene expression, and degradation of junctional proteins. These changes are important since impaired lymphatic function in obesity may contribute to the pathology of obesity in other organ systems in a feed-forward manner by increasing low-grade tissue inflammation and the accumulation of inflammatory cytokines. More importantly, recent studies have suggested that interventions that inhibit inflammatory responses, either pharmacologically or by lifestyle modifications such as aerobic exercise and weight loss, improve lymphatic function and metabolic parameters in obese mice. The purpose of this review is to summarize the pathologic effects of obesity on the lymphatic system, the cellular mechanisms that regulate these responses, the effects of impaired lymphatic function on metabolic syndrome in obesity, and the interventions that may improve lymphatic function in obesity.
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Affiliation(s)
- Raghu P Kataru
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Hyeong Ju Park
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Jung Eun Baik
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Claire Li
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Jinyeon Shin
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Babak J Mehrara
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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48
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Norden PR, Kume T. The Role of Lymphatic Vascular Function in Metabolic Disorders. Front Physiol 2020; 11:404. [PMID: 32477160 PMCID: PMC7232548 DOI: 10.3389/fphys.2020.00404] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/06/2020] [Indexed: 12/13/2022] Open
Abstract
In addition to its roles in the maintenance of interstitial fluid homeostasis and immunosurveillance, the lymphatic system has a critical role in regulating transport of dietary lipids to the blood circulation. Recent work within the past two decades has identified an important relationship between lymphatic dysfunction and patients with metabolic disorders, such as obesity and type 2 diabetes, in part characterized by abnormal lipid metabolism and transport. Utilization of several genetic mouse models, as well as non-genetic models of diet-induced obesity and metabolic syndrome, has demonstrated that abnormal lymphangiogenesis and poor collecting vessel function, characterized by impaired contractile ability and perturbed barrier integrity, underlie lymphatic dysfunction relating to obesity, diabetes, and metabolic syndrome. Despite the progress made by these models, the contribution of the lymphatic system to metabolic disorders remains understudied and new insights into molecular signaling mechanisms involved are continuously developing. Here, we review the current knowledge related to molecular mechanisms resulting in impaired lymphatic function within the context of obesity and diabetes. We discuss the role of inflammation, transcription factor signaling, vascular endothelial growth factor-mediated signaling, and nitric oxide signaling contributing to impaired lymphangiogenesis and perturbed lymphatic endothelial cell barrier integrity, valve function, and contractile ability in collecting vessels as well as their viability as therapeutic targets to correct lymphatic dysfunction and improve metabolic syndromes.
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Affiliation(s)
- Pieter R. Norden
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Tsutomu Kume
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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49
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Parallels of Resistance between Angiogenesis and Lymphangiogenesis Inhibition in Cancer Therapy. Cells 2020; 9:cells9030762. [PMID: 32244922 PMCID: PMC7140636 DOI: 10.3390/cells9030762] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/13/2020] [Accepted: 03/18/2020] [Indexed: 12/24/2022] Open
Abstract
Metastasis is the primary cause of cancer-related mortality. Cancer cells primarily metastasize via blood and lymphatic vessels to colonize lymph nodes and distant organs, leading to worse prognosis. Thus, strategies to limit blood and lymphatic spread of cancer have been a focal point of cancer research for several decades. Resistance to FDA-approved anti-angiogenic therapies designed to limit blood vessel growth has emerged as a significant clinical challenge. However, there are no FDA-approved drugs that target tumor lymphangiogenesis, despite the consequences of metastasis through the lymphatic system. This review highlights several of the key resistance mechanisms to anti-angiogenic therapy and potential challenges facing anti-lymphangiogenic therapy. Blood and lymphatic vessels are more than just conduits for nutrient, fluid, and cancer cell transport. Recent studies have elucidated how these vasculatures often regulate immune responses. Vessels that are abnormal or compromised by tumor cells can lead to immunosuppression. Therapies designed to improve lymphatic vessel function while limiting metastasis may represent a viable approach to enhance immunotherapy and limit cancer progression.
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50
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Ho YC, Srinivasan RS. Lymphatic Vasculature in Energy Homeostasis and Obesity. Front Physiol 2020; 11:3. [PMID: 32038308 PMCID: PMC6987243 DOI: 10.3389/fphys.2020.00003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 01/03/2020] [Indexed: 12/14/2022] Open
Abstract
Obesity is a leading cause of cardiovascular diseases and cancer. Body mass is regulated by the balance between energy uptake and energy expenditure. The etiology of obesity is determined by multiple factors including genetics, nutrient absorption, and inflammation. Lymphatic vasculature is starting to be appreciated as a critical modulator of metabolism and obesity. The primary function of lymphatic vasculature is to maintain interstitial fluid homeostasis. Lymphatic vessels absorb fluids that extravasate from blood vessels and return them to blood circulation. In addition, lymphatic vessels absorb digested lipids from the intestine and regulate inflammation. Hence, lymphatic vessels could be an exciting target for treating obesity. In this article, we will review our current understanding regarding the relationship between lymphatic vasculature and obesity, and highlight some open questions.
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Affiliation(s)
- Yen-Chun Ho
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
| | - R. Sathish Srinivasan
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
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