|
1
|
Rendon CJ, Watts SW, Contreras GA. PVAT adipocyte: energizing, modulating, and structuring vascular function during normotensive and hypertensive states. Am J Physiol Heart Circ Physiol 2025; 328:H1204-H1217. [PMID: 40250838 DOI: 10.1152/ajpheart.00093.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 02/20/2025] [Accepted: 04/11/2025] [Indexed: 04/20/2025]
Abstract
Hypertension represents the most common form of cardiovascular disease. It is characterized by significant remodeling of the various layers of the vascular system, including the outermost layer: the perivascular adipose tissue (PVAT). Given the tissue's pivotal role in regulating blood pressure, a comprehensive understanding of the changes that occur within PVAT during the progression of hypertension is essential. This article reviews the mechanisms through which PVAT modulates blood pressure, including the secretion of bioactive soluble factors, provision of mechanical support, and adipose-specific functions such as adipogenesis, lipogenesis, lipolysis, and extracellular matrix remodeling. Additionally, this review emphasizes the influence of hypertension on each of these regulatory mechanisms, thereby providing a deeper insight into the pathophysiological interplay between hypertension and PVAT biology.
Collapse
Affiliation(s)
- C Javier Rendon
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
| | - Stephanie W Watts
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, United States
| | - G Andres Contreras
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
| |
Collapse
|
|
2
|
Cedars MA, Root KM, Akhaphong B, Beetch M, Miles AE, Regal RR, Alejandro EU, Regal JF. Improved glucose handling in female rat offspring of a hypertensive pregnancy with intrauterine growth restriction. Physiol Rep 2025; 13:e70222. [PMID: 39903552 PMCID: PMC11792987 DOI: 10.14814/phy2.70222] [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: 12/16/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 02/06/2025] Open
Abstract
Hypertensive disorders of pregnancy, intrauterine growth restriction (IUGR), and reduced pancreatic β-cell area increases risk of offspring developing type 2 diabetes (T2D). Our previous studies using rat reduced uteroplacental perfusion pressure (RUPP) model of gestational hypertension and IUGR demonstrated reduced pancreatic β-cell area in offspring at embryonic day 19 and postnatal day 13 (PD13). We hypothesized reduced β-cell area early in life would manifest as hyperglycemia and glucose intolerance as animals aged. However, glucose intolerance did not differ in RUPP versus control offspring to 1 year of life, whether intraperitoneal or oral glucose challenge. At PD28, female RUPP offspring show normalized β-cell area compared to controls and improved ability to clear glucose following oral challenge. Oral glucose challenge results in significant increase in incretin GLP-1 in RUPP female offspring compared to control. Insulin tolerance did not differ amongst control and RUPP offspring, except at PD28 where insulin reduced blood glucose more effectively in RUPP female offspring versus control. Insulin-induced vasodilation in isolated aorta and insulin signaling in fat are more pronounced in RUPP PD28 female offspring versus control. Thus, our studies demonstrate compensatory mechanisms protect IUGR offspring of a hypertensive pregnancy from long-term metabolic effects and development of T2D.
Collapse
Affiliation(s)
- Melissa A. Cedars
- Department of Biomedical SciencesUniversity of Minnesota Medical SchoolDuluthMinnesotaUSA
| | - Kate M. Root
- Department of Biomedical SciencesUniversity of Minnesota Medical SchoolDuluthMinnesotaUSA
| | - Brian Akhaphong
- Department of Integrative Biology and PhysiologyUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
| | - Megan Beetch
- Department of Integrative Biology and PhysiologyUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
| | - Abigail E. Miles
- Department of Biomedical SciencesUniversity of Minnesota Medical SchoolDuluthMinnesotaUSA
| | - Ronald R. Regal
- Department of Mathematics and StatisticsUniversity of MinnesotaDuluthMinnesotaUSA
| | - Emilyn U. Alejandro
- Department of Integrative Biology and PhysiologyUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
| | - Jean F. Regal
- Department of Biomedical SciencesUniversity of Minnesota Medical SchoolDuluthMinnesotaUSA
| |
Collapse
|
|
3
|
Civelek E, Karaman EF, Özden S, Büyükpınarbaşılı N, Uydeş Doğan BS, Kaleli Durman D. Evaluation of the effects of pioglitazone on perivascular adipose tissue function, properties, and structure in a rat model of type-2 diabetes. Can J Physiol Pharmacol 2025; 103:12-28. [PMID: 39361973 DOI: 10.1139/cjpp-2024-0084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
Abstract
Perivascular adipose tissue (PVAT) plays an important role in many physiological and pathological processes, such as regulation of vascular tone. The aim of this study is to evaluate the effects of pioglitazone on functional, structural, and biochemical properties of PVAT in an experimental model of type-2 diabetes (T2DM). T2DM was induced by high-fat-diet/low-dose-streptozotocin in rats, and pioglitazone (20 mg/kg/p.o.) was administered for 6 weeks. Changes in biochemical parameters, PVAT-mass, vascular-reactivity in thoracic-aorta, as well as PVAT adipocytokine and PPARG-expression levels, and histopathology were evaluated. Pioglitazone administration improved blood glucose and lipid profiles in T2DM. Pioglitazone did not change the anticontractile effect of PVAT on aortic contractile reactivity and besides, had no influence on endothelium-dependent and -independent relaxation responses. Pioglitazone administration increased PVAT-mass and tumor necrotizing factor-α levels, while adiponectin, leptin, and interleukin-6 levels were unchanged. Also, a prominent increase was observed in PPARG-expression in T2DM-Pio group. Moreover, pioglitazone decreased liver steatosis, aortic wall thickening, and myocardial damage, whereas increased adipocyte size and adiposity in PVAT. Overall, pioglitazone treatment changed the mass and in part the inflammatory profile of PVAT but did not modify vasoreactivity in T2DM. This study provides novel findings in relationship with the adipogenic effect of pioglitazone and PVAT function.
Collapse
MESH Headings
- Animals
- Pioglitazone/pharmacology
- Pioglitazone/therapeutic use
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Diabetes Mellitus, Type 2/physiopathology
- Adipose Tissue/drug effects
- Adipose Tissue/metabolism
- Adipose Tissue/pathology
- Male
- Rats
- Hypoglycemic Agents/pharmacology
- PPAR gamma/metabolism
- Rats, Wistar
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Blood Glucose/drug effects
- Blood Glucose/metabolism
- Aorta, Thoracic/drug effects
- Aorta, Thoracic/pathology
- Aorta, Thoracic/metabolism
- Aorta, Thoracic/physiopathology
- Adipokines/metabolism
- Disease Models, Animal
Collapse
Affiliation(s)
- Erkan Civelek
- Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey
- Istanbul University, Graduate School of Health Sciences, Istanbul, Turkey
| | - Ecem Fatma Karaman
- Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Istanbul, Turkey
- Biruni University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Istanbul, Turkey
| | - Sibel Özden
- Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Istanbul, Turkey
| | - Nur Büyükpınarbaşılı
- Bezmialem Vakif University, Faculty of Medicine, Department of Medical Pathology, Istanbul, Turkey
| | - B Sönmez Uydeş Doğan
- Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey
| | - Deniz Kaleli Durman
- Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey
| |
Collapse
|
|
4
|
Li J, Tian Z, Zhang T, Jin J, Zhang X, Xie P, Lin H, Gu J, Wu Y, Wang X, Zhang S, Yan X, Guo D, Wang Z, Zhang Q. Single-cell view and a novel protective macrophage subset in perivascular adipose tissue in T2DM. Cell Mol Biol Lett 2024; 29:148. [PMID: 39627688 PMCID: PMC11616190 DOI: 10.1186/s11658-024-00668-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 11/14/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Vasculopathy underlies diabetic complications, with perivascular adipose tissue (PVAT) playing crucial roles in its development. However, the changes in the cellular composition and function of PVAT, including the specific cell subsets and mechanisms implicated in type 2 diabetes mellitus (T2DM) vasculopathy, remain unclear. METHODS To address the above issues, we performed single-cell RNA sequencing on the stromal vascular fraction (SVF) of PVAT from normal and T2DM rats. Then, various bioinformatics tools and functional experiments were used to investigate the characteristic changes in the cellular profile of diabetic PVAT SVF, their implications, and the underlying mechanisms. RESULTS Our study reveals the single-cell landscape of the SVF of PVAT, demonstrating its considerable heterogeneity and significant alterations in T2DM, including an enhanced inflammatory response and elevated proportions of macrophages and natural killer (NK) cells. Moreover, macrophages are critical hubs for cross-talk among various cell populations. Notably, we identified a decreased Pdpn+ macrophage subpopulation in the PVAT of T2DM rats and confirmed this in mice and humans. In vitro and in vivo studies demonstrated that Pdpn+ macrophages alleviated insulin resistance and modulated adipokine/cytokine expression in adipocytes via the Pla2g2d-DHA/EPA-GPR120 pathway. This subset also enhances the function of vascular endothelial and smooth muscle cells, inhibits vascular inflammation and oxidative stress, and improves vasodilatory function, thereby protecting blood vessels. CONCLUSION Pdpn+ macrophages exhibit significant vascular protective effects by alleviating insulin resistance and modulating adipokine/cytokine expression in PVAT adipocytes. This macrophage subtype may therefore play pivotal roles in mitigating vascular complications in T2DM. Our findings also underscore the critical role of immune-metabolic cross-talk in maintaining tissue homeostasis.
Collapse
Affiliation(s)
- Jiaxuan Li
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
- Shandong Provincial Hospital, Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, 250021, China
- Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Chinese Ministry of Education, Shandong First Medical University, Jinan, 250021, China
| | - Zhenyu Tian
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Tongxue Zhang
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Jiajia Jin
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xinjie Zhang
- Department of Biology, University College London, London, NW1 2HE, UK
| | - Panpan Xie
- Department of Breast and Thyroid Surgery, Liaocheng People's Hospital, Liaocheng, 252000, China
| | - Haiyan Lin
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Junfei Gu
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
- Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Yingjie Wu
- Shandong Provincial Hospital, Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, 250021, China
- Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Chinese Ministry of Education, Shandong First Medical University, Jinan, 250021, China
| | - Xiaowei Wang
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Shucui Zhang
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xuefang Yan
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Dong Guo
- Department of Neurology, Liaocheng People's Hospital, Liaocheng, 252000, China.
| | - Zhe Wang
- Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
| | - Qunye Zhang
- Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China.
| |
Collapse
|
|
5
|
Sigdel S, Udoh G, Albalawy R, Wang J. Perivascular Adipose Tissue and Perivascular Adipose Tissue-Derived Extracellular Vesicles: New Insights in Vascular Disease. Cells 2024; 13:1309. [PMID: 39195199 PMCID: PMC11353161 DOI: 10.3390/cells13161309] [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: 07/15/2024] [Revised: 07/29/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024] Open
Abstract
Perivascular adipose tissue (PVAT) is a special deposit of fat tissue surrounding the vasculature. Previous studies suggest that PVAT modulates the vasculature function in physiological conditions and is implicated in the pathogenesis of vascular diseases. Understanding how PVAT influences vasculature function and vascular disease progression is important. Extracellular vesicles (EVs) are novel mediators of intercellular communication. EVs encapsulate molecular cargo such as proteins, lipids, and nucleic acids. EVs can influence cellular functions by transferring the carried bioactive molecules. Emerging evidence indicates that PVAT-derived EVs play an important role in vascular functions under health and disease conditions. This review will focus on the roles of PVAT and PVAT-EVs in obesity, diabetic, and metabolic syndrome-related vascular diseases, offering novel insights into therapeutic targets for vascular diseases.
Collapse
Affiliation(s)
- Smara Sigdel
- Department of Biomedical Sciences, Joan C Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA; (S.S.); (G.U.)
| | - Gideon Udoh
- Department of Biomedical Sciences, Joan C Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA; (S.S.); (G.U.)
| | - Rakan Albalawy
- Department of Internal Medicine, Joan C Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA;
| | - Jinju Wang
- Department of Biomedical Sciences, Joan C Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA; (S.S.); (G.U.)
| |
Collapse
|
|
6
|
Lu T, Zheng Y, Chen X, Lin Z, Liu C, Yuan C. The role of exosome derived miRNAs in inter-cell crosstalk among insulin-related organs in type 2 diabetes mellitus. J Physiol Biochem 2024; 80:501-510. [PMID: 38698251 DOI: 10.1007/s13105-024-01026-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 04/23/2024] [Indexed: 05/05/2024]
Abstract
Exosomes are small extracellular vesicles secreted by almost all cell types, and carry diverse cargo including RNA, and other substances. Recent studies have focused exosomal microRNAs (miRNAs) on various human diseases, including type 2 diabetes mellitus (T2DM) and metabolic syndrome (METS) which accompany the occurrence of insulin resistance. The regulation of insulin signaling has connected with some miRNA expression which play a significant regulatory character in insulin targeted cells or organs, such as fat, muscle, and liver. The miRNAs carried by exosomes, through the circulation in the body fluids, mediate all kinds of physiological and pathological process involved in the human body. Studies have found that exosome derived miRNAs are abnormally expressed and cross-talked with insulin targeted cells or organs to affect insulin pathways. Further investigations of the mechanisms of exosomal miRNAs in T2DM will be valuable for the diagnostic biomarkers and therapeutic targets of T2DM. This review will summarize the molecular mechanism of action of the miRNAs carried by exosomes which are secreted from insulin signaling related cells, and elucidate the pathogenesis of insulin resistance to provide a new strategy for the potential diagnostic biomarkers and therapeutic targets for the type 2 diabetes.
Collapse
Affiliation(s)
- Ting Lu
- Tumor Microenvironment and Immunotherapy Key Laboratory of Hubei province in China, China Three Gorges University, School of Medicine, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Ying Zheng
- Tumor Microenvironment and Immunotherapy Key Laboratory of Hubei province in China, China Three Gorges University, School of Medicine, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Xiaoling Chen
- Tumor Microenvironment and Immunotherapy Key Laboratory of Hubei province in China, China Three Gorges University, School of Medicine, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Zhiyong Lin
- Tumor Microenvironment and Immunotherapy Key Laboratory of Hubei province in China, China Three Gorges University, School of Medicine, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Chaoqi Liu
- Tumor Microenvironment and Immunotherapy Key Laboratory of Hubei province in China, China Three Gorges University, School of Medicine, Yichang, 443002, China.
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
| | - Chengfu Yuan
- Tumor Microenvironment and Immunotherapy Key Laboratory of Hubei province in China, China Three Gorges University, School of Medicine, Yichang, 443002, China.
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China.
- Third-Grade Pharmacological Laboratory on Chinese Medicine Approved by State Administration of Traditional Chinese Medicine, China Three Gorges University, School of Medicine, Yichang, 443002, China.
| |
Collapse
|
|
7
|
Tuttolomondo D, Niccoli G, Martini C, D’Ascenzo F, De Filippo O, Nicolini F, Formica F, Carino D, Gurgoglione FL, Denegri A, Magnani G, Vignali L, De Filippo M, Sverzellati N, Ticinesi A, Bergamaschi L, Pizzi C, Gherbesi E, Suma S, Gaibazzi N. Cardiovascular Disease from Pathophysiology to Risk Estimation: Is Inflammation Estimated through Perivascular Attenuation on Computed Tomography the Key? Life (Basel) 2024; 14:457. [PMID: 38672728 PMCID: PMC11051374 DOI: 10.3390/life14040457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 03/19/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
(1) Background: Systemic inflammation stands as a well-established risk factor for ischemic cardiovascular disease, as well as a contributing factor in the development of cardiac arrhythmias, notably atrial fibrillation. Furthermore, scientific studies have brought to light the pivotal role of localized vascular inflammation in the initiation, progression, and destabilization of coronary atherosclerotic disease. (2) Methods: We comprehensively review recent, yet robust, scientific evidence elucidating the use of perivascular adipose tissue attenuation measurement on computed tomography applied to key anatomical sites. Specifically, the investigation extends to the internal carotid artery, aorta, left atrium, and coronary arteries. (3) Conclusions: The examination of perivascular adipose tissue attenuation emerges as a non-invasive and indirect means of estimating localized perivascular inflammation. This measure is quantified in Hounsfield units, indicative of the inflammatory response elicited by dense adipose tissue near the vessel or the atrium. Particularly noteworthy is its potential utility in assessing inflammatory processes within the coronary arteries, evaluating coronary microvascular dysfunction, appraising conditions within the aorta and carotid arteries, and discerning inflammatory states within the atria, especially in patients with atrial fibrillation. The widespread applicability of perivascular adipose tissue attenuation measurement underscores its significance as a diagnostic tool with considerable potential for enhancing our understanding and management of cardiovascular diseases.
Collapse
Affiliation(s)
- Domenico Tuttolomondo
- Department of Cardiology, Parma University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Giampaolo Niccoli
- Department of Cardiology, Parma University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Chiara Martini
- Department of Diagnostic, Parma University Hospital, 43126 Parma, Italy
- Department of Medicine and Surgery, University of Parma, Via Antonio Gramsci 14, 43126 Parma, Italy
| | - Fabrizio D’Ascenzo
- Division of Cardiology, Cardiovascular and Thoracic Department, Città della Salute e della Scienza, 10126 Turin, Italy
| | - Ovidio De Filippo
- Division of Cardiology, Cardiovascular and Thoracic Department, Città della Salute e della Scienza, 10126 Turin, Italy
| | - Francesco Nicolini
- Department of Cardiac Surgery, Parma University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Francesco Formica
- Department of Cardiac Surgery, Parma University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Davide Carino
- Department of Cardiac Surgery, Parma University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | | | - Andrea Denegri
- Department of Cardiology, Parma University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Giulia Magnani
- Department of Cardiology, Parma University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Luigi Vignali
- Department of Cardiology, Parma University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Massimo De Filippo
- Department of Medicine and Surgery (DiMec), Section of Radiology, University of Parma, Maggiore Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Nicola Sverzellati
- Scienze Radiologiche, Dipartimento di Medicina e Chirurgia, University-Hospital of Parma, 43126 Parma, Italy
| | - Andrea Ticinesi
- Department of Medicine and Surgery, University of Parma, Via Antonio Gramsci 14, 43126 Parma, Italy
- Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy
| | - Luca Bergamaschi
- Cardiology Unit, IRCCS Azienda Ospedaliera-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences—DIMEC—Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
| | - Carmine Pizzi
- Cardiology Unit, IRCCS Azienda Ospedaliera-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences—DIMEC—Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
| | - Elisa Gherbesi
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20154 Milan, Italy
| | - Sergio Suma
- Department of Cardiology, Parma University Hospital, Via Gramsci 14, 43126 Parma, Italy
| | - Nicola Gaibazzi
- Department of Cardiology, Parma University Hospital, Via Gramsci 14, 43126 Parma, Italy
| |
Collapse
|
|
8
|
Valentini A, Cardillo C, Della Morte D, Tesauro M. The Role of Perivascular Adipose Tissue in the Pathogenesis of Endothelial Dysfunction in Cardiovascular Diseases and Type 2 Diabetes Mellitus. Biomedicines 2023; 11:3006. [PMID: 38002006 PMCID: PMC10669084 DOI: 10.3390/biomedicines11113006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/27/2023] [Accepted: 11/05/2023] [Indexed: 11/26/2023] Open
Abstract
Cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) are two of the four major chronic non-communicable diseases (NCDs) representing the leading cause of death worldwide. Several studies demonstrate that endothelial dysfunction (ED) plays a central role in the pathogenesis of these chronic diseases. Although it is well known that systemic chronic inflammation and oxidative stress are primarily involved in the development of ED, recent studies have shown that perivascular adipose tissue (PVAT) is implicated in its pathogenesis, also contributing to the progression of atherosclerosis and to insulin resistance (IR). In this review, we describe the relationship between PVAT and ED, and we also analyse the role of PVAT in the pathogenesis of CVDs and T2DM, further assessing its potential therapeutic target with the aim of restoring normal ED and reducing global cardiovascular risk.
Collapse
Affiliation(s)
- Alessia Valentini
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; (A.V.); (D.D.M.)
| | - Carmine Cardillo
- Department of Aging, Policlinico A. Gemelli IRCCS, 00168 Roma, Italy;
- Department of Translational Medicine and Surgery, Catholic University, 00168 Rome, Italy
| | - David Della Morte
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; (A.V.); (D.D.M.)
| | - Manfredi Tesauro
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; (A.V.); (D.D.M.)
| |
Collapse
|
|
9
|
Shi H, Wu H, Winkler MA, Belin de Chantemèle EJ, Lee R, Kim HW, Weintraub NL. Perivascular adipose tissue in autoimmune rheumatic diseases. Pharmacol Res 2022; 182:106354. [PMID: 35842184 PMCID: PMC10184774 DOI: 10.1016/j.phrs.2022.106354] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/27/2022] [Accepted: 07/11/2022] [Indexed: 01/14/2023]
Abstract
Perivascular adipose tissue (PVAT) resides at the outermost boundary of the vascular wall, surrounding most conduit blood vessels, except for the cerebral vessels, in humans. A growing body of evidence suggests that inflammation localized within PVAT may contribute to the pathogenesis of cardiovascular disease (CVD). Patients with autoimmune rheumatic diseases (ARDs), e.g., systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriasis, etc., exhibit heightened systemic inflammation and are at increased risk for CVD. Data from clinical studies in patients with ARDs support a linkage between dysfunctional adipose tissue, and PVAT in particular, in disease pathogenesis. Here, we review the data linking PVAT to the pathogenesis of CVD in patients with ARDs, focusing on the role of novel PVAT imaging techniques in defining disease risk and responses to biological therapies.
Collapse
Affiliation(s)
- Hong Shi
- Division of Rheumatology, Medical College of Georgia at Augusta University, Augusta, GA, USA; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Hanping Wu
- Department of Radiology and Imaging, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Michael A Winkler
- Department of Radiology and Imaging, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Eric J Belin de Chantemèle
- Division of Cardiology, Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Richard Lee
- Department of Surgery, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Ha Won Kim
- Division of Cardiology, Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Neal L Weintraub
- Division of Cardiology, Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA.
| |
Collapse
|
|
10
|
Hillock-Watling C, Gotlieb AI. The pathobiology of perivascular adipose tissue (PVAT), the fourth layer of the blood vessel wall. Cardiovasc Pathol 2022; 61:107459. [PMID: 35907442 DOI: 10.1016/j.carpath.2022.107459] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/24/2022] [Accepted: 07/21/2022] [Indexed: 12/21/2022] Open
Abstract
The perivascular adipose tissue (PVAT) is an adipose tissue depot which surrounds most human blood vessels. It is metabolically active and has both a protective and a pathogenic role in vascular biology and pathobiology. It regulates vascular homeostasis and promotes vascular dysfunction. The purpose of this review is to consider the origin, structure, function, and dysfunction of this unique adipose depot consisting of white (WAT), brown (BAT) and beige adipose tissue, to support the concept that PVAT may be considered the fourth layer of the normal arterial wall (tunica adiposa), in which dysfunction creates a microenvironment that regulates, in part, the initiation and growth of the fibro-inflammatory lipid atherosclerotic plaque. Experimental in-vivo and in-vitro studies and human investigations show that the adipocytes, extracellular matrix, nerve fibers and vasa vasorum found in PVAT form a functional adipose tissue unit adjacent to, but not anatomically separated from, the adventitia. PVAT maintains and regulates the structure and function of the normal arterial wall through autocrine and paracrine mechanisms, that include modulation of medial smooth muscle cell contractility and secretion of anti-inflammatory molecules. PVAT shows regional phenotypic heterogeneity which may be important in its effect on the wall of specific sections of the aorta and its muscular branches during perturbations and various injuries including obesity and diabetes. In atherosclerosis, a pan-vascular microenvironment is created that functionally links the intima-medial atherosclerotic plaque to the adventitia and PVAT beneath the plaque, highlighting the local impact of PVAT on atherogenesis. PVAT adipocytes have inflammatory effects which in response to injury show activation and phenotypic changes, some of which are considered to have direct and indirect effects on the intima and media during the initiation, growth, and development of complicated atherosclerotic plaques. Thus, it is important to maintain the integrity of the full vascular microenvironment so that design of experimental and human studies include investigation of PVAT. The era of discarding PVAT tissue in both experimental and human research and clinical vascular studies should end.
Collapse
Affiliation(s)
- Cassie Hillock-Watling
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Avrum I Gotlieb
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
11
|
Dwaib HS, AlZaim I, Ajouz G, Eid AH, El-Yazbi A. Sex Differences in Cardiovascular Impact of Early Metabolic Impairment: Interplay between Dysbiosis and Adipose Inflammation. Mol Pharmacol 2022; 102:481-500. [PMID: 34732528 DOI: 10.1124/molpharm.121.000338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 10/23/2021] [Indexed: 11/22/2022] Open
Abstract
The evolving view of gut microbiota has shifted toward describing the colonic flora as a dynamic organ in continuous interaction with systemic physiologic processes. Alterations of the normal gut bacterial profile, known as dysbiosis, has been linked to a wide array of pathologies. Of particular interest is the cardiovascular-metabolic disease continuum originating from positive energy intake and high-fat diets. Accumulating evidence suggests a role for sex hormones in modulating the gut microbiome community. Such a role provides an additional layer of modulation of the early inflammatory changes culminating in negative metabolic and cardiovascular outcomes. In this review, we will shed the light on the role of sex hormones in cardiovascular dysfunction mediated by high-fat diet-induced dysbiosis, together with the possible involvement of insulin resistance and adipose tissue inflammation. Insights into novel therapeutic interventions will be discussed as well. SIGNIFICANCE STATEMENT: Increasing evidence implicates a role for dysbiosis in the cardiovascular complications of metabolic dysfunction. This minireview summarizes the available data on the sex-based differences in gut microbiota alterations associated with dietary patterns leading to metabolic impairment. A role for a differential impact of adipose tissue inflammation across sexes in mediating the cardiovascular detrimental phenotype following diet-induced dysbiosis is proposed. Better understanding of this pathway will help introduce early approaches to mitigate cardiovascular deterioration in metabolic disease.
Collapse
Affiliation(s)
- Haneen S Dwaib
- Department of Pharmacology and Toxicology, Faculty of Medicine (H.S.D., I.A., G.A., A.E.-Y.), Department of Nutrition and Food Sciences, Faculty of Agricultural and Food Sciences (H.S.D.), American University of Beirut, Beirut, Lebanon; Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon (I.A.); Department of Basic Medical Sciences, College of Medicine (A.H.E.), Biomedical and Pharmaceutical Research Unit, QU Health (A.H.E.), Qatar University, Doha, Qatar; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.E.-Y.); and Faculty of Pharmacy, Alalamein International University, Alalamein, Egypt (A.E.-Y.)
| | - Ibrahim AlZaim
- Department of Pharmacology and Toxicology, Faculty of Medicine (H.S.D., I.A., G.A., A.E.-Y.), Department of Nutrition and Food Sciences, Faculty of Agricultural and Food Sciences (H.S.D.), American University of Beirut, Beirut, Lebanon; Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon (I.A.); Department of Basic Medical Sciences, College of Medicine (A.H.E.), Biomedical and Pharmaceutical Research Unit, QU Health (A.H.E.), Qatar University, Doha, Qatar; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.E.-Y.); and Faculty of Pharmacy, Alalamein International University, Alalamein, Egypt (A.E.-Y.)
| | - Ghina Ajouz
- Department of Pharmacology and Toxicology, Faculty of Medicine (H.S.D., I.A., G.A., A.E.-Y.), Department of Nutrition and Food Sciences, Faculty of Agricultural and Food Sciences (H.S.D.), American University of Beirut, Beirut, Lebanon; Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon (I.A.); Department of Basic Medical Sciences, College of Medicine (A.H.E.), Biomedical and Pharmaceutical Research Unit, QU Health (A.H.E.), Qatar University, Doha, Qatar; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.E.-Y.); and Faculty of Pharmacy, Alalamein International University, Alalamein, Egypt (A.E.-Y.)
| | - Ali H Eid
- Department of Pharmacology and Toxicology, Faculty of Medicine (H.S.D., I.A., G.A., A.E.-Y.), Department of Nutrition and Food Sciences, Faculty of Agricultural and Food Sciences (H.S.D.), American University of Beirut, Beirut, Lebanon; Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon (I.A.); Department of Basic Medical Sciences, College of Medicine (A.H.E.), Biomedical and Pharmaceutical Research Unit, QU Health (A.H.E.), Qatar University, Doha, Qatar; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.E.-Y.); and Faculty of Pharmacy, Alalamein International University, Alalamein, Egypt (A.E.-Y.)
| | - Ahmed El-Yazbi
- Department of Pharmacology and Toxicology, Faculty of Medicine (H.S.D., I.A., G.A., A.E.-Y.), Department of Nutrition and Food Sciences, Faculty of Agricultural and Food Sciences (H.S.D.), American University of Beirut, Beirut, Lebanon; Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon (I.A.); Department of Basic Medical Sciences, College of Medicine (A.H.E.), Biomedical and Pharmaceutical Research Unit, QU Health (A.H.E.), Qatar University, Doha, Qatar; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.E.-Y.); and Faculty of Pharmacy, Alalamein International University, Alalamein, Egypt (A.E.-Y.)
| |
Collapse
|
|
12
|
Kahn DE, Bergman BC. Keeping It Local in Metabolic Disease: Adipose Tissue Paracrine Signaling and Insulin Resistance. Diabetes 2022; 71:599-609. [PMID: 35316835 PMCID: PMC8965661 DOI: 10.2337/dbi21-0020] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 01/03/2022] [Indexed: 01/04/2023]
Abstract
Alterations in adipose tissue composition and function are associated with obesity and contribute to the development of type 2 diabetes. While the significance of this relationship has been cemented, our understanding of the multifaceted role of adipose tissue in metabolic heath and disease continues to evolve and expand. Heterogenous populations of cells that make up adipose tissue throughout the body generate diverse secretomes containing a mosaic of bioactive compounds with vast structural and signaling capabilities. While there are many reports highlighting the important role of adipose tissue endocrine signaling in insulin resistance and type 2 diabetes, the direct, local, paracrine effect of adipose tissue has received less attention. Recent studies have begun to underscore the importance of considering anatomically discrete adipose depots for their specific impact on local microenvironments and metabolic function in neighboring tissues as well as regulation of whole-body physiology. This article highlights the important role of adipose tissue paracrine signaling on metabolic function and insulin sensitivity in nearby tissues and organs, specifically focusing on visceral, pancreatic, subcutaneous, intermuscular, and perivascular adipose tissue depots.
Collapse
Affiliation(s)
- Darcy E. Kahn
- University of Colorado Anschutz Medical Campus, Aurora, CO
| | | |
Collapse
|
|
13
|
Weerts J, Mourmans SGJ, Barandiarán Aizpurua A, Schroen BLM, Knackstedt C, Eringa E, Houben AJHM, van Empel VPM. The Role of Systemic Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction. Biomolecules 2022; 12:biom12020278. [PMID: 35204779 PMCID: PMC8961612 DOI: 10.3390/biom12020278] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/01/2022] [Accepted: 02/05/2022] [Indexed: 02/06/2023] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing incidence, leading to a health care problem of epidemic proportions for which no curative treatments exist. Consequently, an urge exists to better understand the pathophysiology of HFpEF. Accumulating evidence suggests a key pathophysiological role for coronary microvascular dysfunction (MVD), with an underlying mechanism of low-grade pro-inflammatory state caused by systemic comorbidities. The systemic entity of comorbidities and inflammation in HFpEF imply that patients develop HFpEF due to systemic mechanisms causing coronary MVD, or systemic MVD. The absence or presence of peripheral MVD in HFpEF would reflect HFpEF being predominantly a cardiac or a systemic disease. Here, we will review the current state of the art of cardiac and systemic microvascular dysfunction in HFpEF (Graphical Abstract), resulting in future perspectives on new diagnostic modalities and therapeutic strategies.
Collapse
Affiliation(s)
- Jerremy Weerts
- Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands; (S.G.J.M.); (A.B.A.); (B.L.M.S.); (C.K.); (V.P.M.v.E.)
- Correspondence: ; Tel.: +31-43-387-7097
| | - Sanne G. J. Mourmans
- Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands; (S.G.J.M.); (A.B.A.); (B.L.M.S.); (C.K.); (V.P.M.v.E.)
| | - Arantxa Barandiarán Aizpurua
- Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands; (S.G.J.M.); (A.B.A.); (B.L.M.S.); (C.K.); (V.P.M.v.E.)
| | - Blanche L. M. Schroen
- Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands; (S.G.J.M.); (A.B.A.); (B.L.M.S.); (C.K.); (V.P.M.v.E.)
| | - Christian Knackstedt
- Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands; (S.G.J.M.); (A.B.A.); (B.L.M.S.); (C.K.); (V.P.M.v.E.)
| | - Etto Eringa
- Department of Physiology, CARIM School for Cardiovascular Diseases, Maastricht University, 6211 LK Maastricht, The Netherlands;
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Alfons J. H. M. Houben
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands;
| | - Vanessa P. M. van Empel
- Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands; (S.G.J.M.); (A.B.A.); (B.L.M.S.); (C.K.); (V.P.M.v.E.)
| |
Collapse
|
|
14
|
Rukavina Mikusic NL, Kouyoumdzian NM, Puyó AM, Fernández BE, Choi MR. Role of natriuretic peptides in the cardiovascular-adipose communication: a tale of two organs. Pflugers Arch 2022; 474:5-19. [PMID: 34173888 DOI: 10.1007/s00424-021-02596-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 05/31/2021] [Accepted: 06/11/2021] [Indexed: 12/23/2022]
Abstract
Natriuretic peptides have long been known for their cardiovascular function. However, a growing body of evidence emphasizes the role of natriuretic peptides in the energy metabolism of several substrates in humans and animals, thus interrelating the heart, as an endocrine organ, with various insulin-sensitive tissues and organs such as adipose tissue, muscle skeletal, and liver. Adipose tissue dysfunction is associated with altered regulation of the natriuretic peptide system, also indicated as a natriuretic disability. Evidence points to a contribution of this natriuretic disability to the development of obesity, type 2 diabetes mellitus, and cardiometabolic complications; although the causal relationship is not fully understood at present. However, targeting the natriuretic peptide pathway may improve metabolic health in obesity and type 2 diabetes mellitus. This review will focus on the current literature on the metabolic functions of natriuretic peptides with emphasis on lipid metabolism and insulin sensitivity. Natriuretic peptide system alterations could be proposed as one of the linking mechanisms between adipose tissue dysfunction and cardiovascular disease.
Collapse
Affiliation(s)
- Natalia Lucía Rukavina Mikusic
- Departamento de Ciencias Biológicas, Cátedra de Anatomía e Histología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
| | - Nicolás Martín Kouyoumdzian
- Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ana María Puyó
- Departamento de Ciencias Biológicas, Cátedra de Anatomía e Histología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | | | - Marcelo Roberto Choi
- Departamento de Ciencias Biológicas, Cátedra de Anatomía e Histología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto Universitario de Ciencias de la Salud, Fundación H.A. Barceló, Buenos Aires, Argentina
| |
Collapse
|
|
15
|
Wang Y, Yildiz F, Struve A, Kassmann M, Markó L, Köhler MB, Luft FC, Gollasch M, Tsvetkov D. Aging Affects K V7 Channels and Perivascular Adipose Tissue-Mediated Vascular Tone. Front Physiol 2021; 12:749709. [PMID: 34899382 PMCID: PMC8662361 DOI: 10.3389/fphys.2021.749709] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/26/2021] [Indexed: 12/04/2022] Open
Abstract
Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3–5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3–5 channels represent a promising target in cardiovascular aging.
Collapse
Affiliation(s)
- Yibin Wang
- Charité Medical Faculty, Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
| | - Fatima Yildiz
- Faculty of Medicine, Istanbul Medeniyet University, Istanbul, Turkey
| | - Andrey Struve
- Department of Ear, Throat and Nose Diseases, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Mario Kassmann
- Charité Medical Faculty, Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,Department of Internal Medicine and Geriatrics, University Medicine Greifswald, Greifswald, Germany
| | - Lajos Markó
- Charité Medical Faculty, Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
| | - May-Britt Köhler
- Charité Medical Faculty, Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
| | - Friedrich C Luft
- Charité Medical Faculty, Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
| | - Maik Gollasch
- Charité Medical Faculty, Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,Department of Internal Medicine and Geriatrics, University Medicine Greifswald, Greifswald, Germany
| | - Dmitry Tsvetkov
- Charité Medical Faculty, Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,Department of Internal Medicine and Geriatrics, University Medicine Greifswald, Greifswald, Germany
| |
Collapse
|
|
16
|
Kunath A, Unosson J, Friederich-Persson M, Bjarnegård N, Becirovic-Agic M, Björck M, Mani K, Wanhainen A, Wågsäter D. Inhibition of angiotensin-induced aortic aneurysm by metformin in apolipoprotein E-deficient mice. JVS Vasc Sci 2021; 2:33-42. [PMID: 34617056 PMCID: PMC8489247 DOI: 10.1016/j.jvssci.2020.11.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/30/2020] [Indexed: 10/26/2022] Open
Abstract
Objective Metformin is associated with a reduced incidence and growth of abdominal aortic aneurysms (AAAs). The aim of the present study was to investigate the inhibitory effects of metformin on AAA development and possible underlying mechanisms in experimentally induced AAAs in mice, along with the possible synergistic effects of metformin and imatinib. Methods Angiotensin II was used to induce AAAs in apolipoprotein E knockout (ApoE -/- ) mice for 28 days. The mice were treated with metformin (n = 11), metformin combined with imatinib (n = 7), or vehicle (n = 12), starting 3 days before angiotensin II infusion. Ultrasound examination was used to analyze aneurysm formation. Cholesterol and blood pressure levels were measured at the start and end of the study. Gene array and quantitative polymerase chain reaction were used to analyze the changes in gene expression in the aorta. Wire myography was used to study vascular function. Results Metformin (n = 11) suppressed the formation and progression of AAAs by 50% compared with the vehicle controls (n = 12), with no further effects from imatinib (n = 7). Metformin reduced total cholesterol and mRNA expression of SPP1 (encoding osteopontin), MMP12, and the glycoprotein genes Gpnmb and Clec7a. Furthermore, metformin inhibited blood pressure increases and reduced vascular contractions, as determined by wire myography, and restored the anticontractile function of perivascular adipose tissue. Conclusion Metformin inhibited aneurysm formation and progression and normalized vascular function in ApoE -/- mice with no additional effect of imatinib. This might be mediated by the protective effects on vascular endothelial function and perivascular adipose tissue via reduced expression of genes promoting inflammation, including SPP1, MMP12, Gpnmb, and Clec7a. Clinical relevance Retrospective studies of the effects of metformin in patients with aneurysm have so far only been performed of those with type 2 diabetes. The present study shows that metformin has effects on nondiabetic mice and revealed the mechanistic effects mediated by the drug that could also be important to study as outcomes in humans. Future clinical trials using metformin are warranted in patients without diabetes with abdominal aortic aneurysms.
Collapse
Affiliation(s)
- Anne Kunath
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.,Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Jon Unosson
- Section of Vascular Surgery, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Niclas Bjarnegård
- Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | | | - Martin Björck
- Section of Vascular Surgery, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Kevin Mani
- Section of Vascular Surgery, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Anders Wanhainen
- Section of Vascular Surgery, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Dick Wågsäter
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.,Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| |
Collapse
|
|
17
|
Tuttolomondo D, Martini C, Nicolini F, Formica F, Pini A, Secchi F, Volpi R, De Filippo M, Gaibazzi N. Perivascular Adipose Tissue Attenuation on Computed Tomography beyond the Coronary Arteries. A Systematic Review. Diagnostics (Basel) 2021; 11:diagnostics11081495. [PMID: 34441429 PMCID: PMC8393555 DOI: 10.3390/diagnostics11081495] [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: 07/12/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 12/05/2022] Open
Abstract
(1) Background: Perivascular adipose tissue attenuation, measured with computed tomography imaging, is a marker of mean local vascular inflammation since it reflects the morphological changes of the fat tissue in direct contact with the vessel. This method is thoroughly validated in coronary arteries, but few studies have been performed in other vascular beds. The aim of the present study is to provide insight into the potential application of perivascular adipose tissue attenuation through computed tomography imaging in extra-coronary arteries. (2) Methods: A comprehensive search of the scientific literature published in the last 30 years (1990–2020) has been performed on Medline. (3) Results: A Medline databases search for titles, abstracts, and keywords returned 3251 records. After the exclusion of repetitions and the application of inclusion and exclusion criteria and abstract screening, 37 studies were selected for full-text evaluation. Three papers were finally included in the systematic review. Perivascular adipose tissue attenuation assessment was studied in the internal carotid artery, ascending thoracic aorta, and abdominal aorta. (4) Conclusions: Perivascular adipose tissue attenuation seems to be an applicable parameter in all investigated vascular beds, generally with good inter-observer reproducibility.
Collapse
Affiliation(s)
- Domenico Tuttolomondo
- Department of Cardiology, Parma University Hospital, Via Gramsci 14, 43125 Parma, Italy; (D.T.); (N.G.)
| | - Chiara Martini
- Department of Radiology, Parma University Hospital, Via Gramsci 14, 43125 Parma, Italy
- Correspondence: ; Tel.: +39-3457245174
| | - Francesco Nicolini
- Department of Cardiac Surgery, Parma University Hospital, Via Gramsci 14, 43125 Parma, Italy; (F.N.); (F.F.)
| | - Francesco Formica
- Department of Cardiac Surgery, Parma University Hospital, Via Gramsci 14, 43125 Parma, Italy; (F.N.); (F.F.)
| | - Alessandro Pini
- Cardiovascular-Genetic Center, IRCCS Policlinico San Donato, 20097 Milano, Italy;
| | - Francesco Secchi
- Department of Radiology, IRCCS Policlinico San Donato, 20097 Milano, Italy;
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milano, Italy
| | - Riccardo Volpi
- Department of Medicine and Surgery, Medical Clinic, University of Parma, Maggiore Hospital, Via Gramsci 14, 43125 Parma, Italy;
| | - Massimo De Filippo
- Department of Medicine and Surgery, Section of Radiology, University of Parma, Maggiore Hospital, Via Gramsci 14, 43125 Parma, Italy;
| | - Nicola Gaibazzi
- Department of Cardiology, Parma University Hospital, Via Gramsci 14, 43125 Parma, Italy; (D.T.); (N.G.)
| |
Collapse
|
|
18
|
Wang M, Xing J, Liu M, Gao M, Liu Y, Li X, Hu L, Zhao X, Liao J, Liu G, Dong J. Deletion of Seipin Attenuates Vascular Function and the Anticontractile Effect of Perivascular Adipose Tissue. Front Cardiovasc Med 2021; 8:706924. [PMID: 34409079 PMCID: PMC8365033 DOI: 10.3389/fcvm.2021.706924] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 07/13/2021] [Indexed: 11/13/2022] Open
Abstract
Seipin locates in endoplasmic reticulum (ER) and regulates adipogenesis and lipid droplet formation. Deletion of Seipin has been well-demonstrated to cause severe general lipodystrophy, however, its role in maintaining perivascular adipose tissue (PVAT) and vascular homeostasis has not been directly assessed. In the present study, we investigated the role of Seipin in mediating the anticontractile effect of PVAT and vascular function. Seipin expression in PVAT and associated vessels were detected by qPCR and western-blot. Seipin is highly expressed in PVAT, but hardly in vessels. Structural and functional alterations of PVAT and associated vessels were compared between Seipin -/- mice and WT mice. In Seipin -/- mice, aortic and mesenteric PVAT were significantly reduced in mass and adipose-derived relaxing factors (ADRFs) secretion, but increased in macrophage infiltration and ER stress, as compared with those in WT mice. Aortic and mesenteric artery rings from WT and Seipin -/- mice were mounted on a wire myograph. Vasoconstriction and vasodilation were studied in vessels with and without PVAT. WT PVAT augmented relaxation but not Seipin -/- PVAT, which suggest impaired anticontractile function in PVAT of Seipin -/- mice. Thoracic aorta and mesenteric artery from Seipin -/- mice had impaired contractility in response to phenylephrine (PHE) and relaxation to acetylcholine (Ach). In conclusion, Seipin deficiency caused abnormalities in PVAT morphology and vascular functions. Our data demonstrated for the first time that Seipin plays a critical role in maintaining PVAT function and vascular homeostasis.
Collapse
Affiliation(s)
- Mengyu Wang
- Department of Cardiology, Henan Key Laboratory of Hereditary Cardiovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Junhui Xing
- Department of Cardiology, Henan Key Laboratory of Hereditary Cardiovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengduan Liu
- Department of Cardiology, Henan Key Laboratory of Hereditary Cardiovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mingming Gao
- Laboratory of Lipid Metabolism, Hebei Medical University, Shijiazhuang, China
| | - Yangyang Liu
- Department of Cardiology, Henan Key Laboratory of Hereditary Cardiovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaowei Li
- Department of Cardiology, Henan Key Laboratory of Hereditary Cardiovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liang Hu
- Department of Cardiology, Henan Key Laboratory of Hereditary Cardiovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyan Zhao
- Department of Cardiology, Henan Key Laboratory of Hereditary Cardiovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiawei Liao
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - George Liu
- Key Laboratory of Molecular Cardiovascular Sciences, Peking University Health Science Center, School of Basic Medical Sciences, Institute of Cardiovascular Sciences, Ministry of Education, Beijing, China
| | - Jianzeng Dong
- Department of Cardiology, Henan Key Laboratory of Hereditary Cardiovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Cardiology, National Clinical Research Centre for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
19
|
Sowka A, Dobrzyn P. Role of Perivascular Adipose Tissue-Derived Adiponectin in Vascular Homeostasis. Cells 2021; 10:cells10061485. [PMID: 34204799 PMCID: PMC8231548 DOI: 10.3390/cells10061485] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/04/2021] [Accepted: 06/08/2021] [Indexed: 12/27/2022] Open
Abstract
Studies of adipose tissue biology have demonstrated that adipose tissue should be considered as both passive, energy-storing tissue and an endocrine organ because of the secretion of adipose-specific factors, called adipokines. Adiponectin is a well-described homeostatic adipokine with metabolic properties. It regulates whole-body energy status through the induction of fatty acid oxidation and glucose uptake. Adiponectin also has anti-inflammatory and antidiabetic properties, making it an interesting subject of biomedical studies. Perivascular adipose tissue (PVAT) is a fat depot that is conterminous to the vascular wall and acts on it in a paracrine manner through adipokine secretion. PVAT-derived adiponectin can act on the vascular wall through endothelial cells and vascular smooth muscle cells. The present review describes adiponectin's structure, receptors, and main signaling pathways. We further discuss recent studies of the extent and nature of crosstalk between PVAT-derived adiponectin and endothelial cells, vascular smooth muscle cells, and atherosclerotic plaques. Furthermore, we argue whether adiponectin and its receptors may be considered putative therapeutic targets.
Collapse
|
|
20
|
Moraes RDA, Webb RC, Silva DF. Vascular Dysfunction in Diabetes and Obesity: Focus on TRP Channels. Front Physiol 2021; 12:645109. [PMID: 33716794 PMCID: PMC7952965 DOI: 10.3389/fphys.2021.645109] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/09/2021] [Indexed: 01/22/2023] Open
Abstract
Transient receptor potential (TRP) superfamily consists of a diverse group of non-selective cation channels that has a wide tissue distribution and is involved in many physiological processes including sensory perception, secretion of hormones, vasoconstriction/vasorelaxation, and cell cycle modulation. In the blood vessels, TRP channels are present in endothelial cells, vascular smooth muscle cells, perivascular adipose tissue (PVAT) and perivascular sensory nerves, and these channels have been implicated in the regulation of vascular tone, vascular cell proliferation, vascular wall permeability and angiogenesis. Additionally, dysfunction of TRP channels is associated with cardiometabolic diseases, such as diabetes and obesity. Unfortunately, the prevalence of diabetes and obesity is rising worldwide, becoming an important public health problems. These conditions have been associated, highlighting that obesity is a risk factor for type 2 diabetes. As well, both cardiometabolic diseases have been linked to a common disorder, vascular dysfunction. In this review, we briefly consider general aspects of TRP channels, and we focus the attention on TRPC (canonical or classical), TRPV (vanilloid), TRPM (melastatin), and TRPML (mucolipin), which were shown to be involved in vascular alterations of diabetes and obesity or are potentially linked to vascular dysfunction. Therefore, elucidation of the functional and molecular mechanisms underlying the role of TRP channels in vascular dysfunction in diabetes and obesity is important for the prevention of vascular complications and end-organ damage, providing a further therapeutic target in the treatment of these metabolic diseases.
Collapse
Affiliation(s)
- Raiana Dos Anjos Moraes
- Laboratory of Cardiovascular Physiology and Pharmacology, Institute of Health Sciences, Federal University of Bahia, Salvador, Brazil.,Postgraduate Course in Biotechnology in Health and Investigative Medicine, Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil
| | - R Clinton Webb
- Department of Cell Biology and Anatomy and Cardiovascular Translational Research Center, University of South Carolina, Columbia, SC, United States
| | - Darízy Flávia Silva
- Laboratory of Cardiovascular Physiology and Pharmacology, Institute of Health Sciences, Federal University of Bahia, Salvador, Brazil.,Postgraduate Course in Biotechnology in Health and Investigative Medicine, Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil
| |
Collapse
|
|
21
|
Saxton SN, Toms LK, Aldous RG, Withers SB, Ohanian J, Heagerty AM. Restoring Perivascular Adipose Tissue Function in Obesity Using Exercise. Cardiovasc Drugs Ther 2021; 35:1291-1304. [PMID: 33687595 PMCID: PMC8578065 DOI: 10.1007/s10557-020-07136-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/21/2020] [Indexed: 12/24/2022]
Abstract
Purpose Perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and β3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function. Methods Vascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of β3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT. Results High fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via β3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing β3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored. Conclusion Loss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity. Supplementary Information The online version contains supplementary material available at 10.1007/s10557-020-07136-0.
Collapse
Affiliation(s)
- Sophie N Saxton
- Division of Cardiovascular Sciences, University of Manchester, Manchester, UK
- The Lydia Becker Institute of Immunology & Inflammation, University of Manchester, Manchester, UK
| | - Lauren K Toms
- Division of Cardiovascular Sciences, University of Manchester, Manchester, UK
| | | | - Sarah B Withers
- Division of Cardiovascular Sciences, University of Manchester, Manchester, UK
- The Lydia Becker Institute of Immunology & Inflammation, University of Manchester, Manchester, UK
- School of Science, Engineering and Environment, University of Salford, Salford, UK
| | - Jacqueline Ohanian
- Division of Cardiovascular Sciences, University of Manchester, Manchester, UK
| | - Anthony M Heagerty
- Division of Cardiovascular Sciences, University of Manchester, Manchester, UK.
- The Lydia Becker Institute of Immunology & Inflammation, University of Manchester, Manchester, UK.
- Division of Cardiovascular Sciences, Manchester Academic Health Science Centre, Core Technology Facility (3rd floor), 46 Grafton Street, Manchester, M13 9NT, UK.
| |
Collapse
|
|
22
|
|
|
23
|
Musale V, Moffett RC, Conlon JM, Flatt PR, Abdel-Wahab YH. Beneficial actions of the [A14K] analog of the frog skin peptide PGLa-AM1 in mice with obesity and degenerative diabetes: A mechanistic study. Peptides 2021; 136:170472. [PMID: 33338546 DOI: 10.1016/j.peptides.2020.170472] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/15/2022]
Abstract
The antidiabetic actions of [A14K]PGLa-AM1, an analog of peptide glycine-leucine-amide-AM1 isolated from skin secretions of the octoploid frog Xenopus amieti, were investigated in genetically diabetic-obese db/db mice. Twice daily administration of [A14K]PGLa-AM1 (75 nmol/kg body weight) for 28 days significantly (P < 0.05) decreased circulating blood glucose and HbA1c and increased plasma insulin concentrations leading to improvements in glucose tolerance. The elevated levels of triglycerides, LDL and cholesterol associated with the db/db phenotype were significantly reduced by peptide administration. Elevated plasma alanine transaminase, aspartic acid transaminase, and alkaline phosphatase activities and creatinine concentrations were also significantly decreased. Peptide treatment increased pancreatic insulin content and improved the responses of isolated islets to established insulin secretagogues. No significant changes in islet β-cell and α-cell areas were observed in [A14K]PGLa-AM1 treated mice but the loss of large and medium-size islets was prevented. Peptide administration resulted in a significant (P < 0.01) increase in islet expression of the gene encoding Pdx-1, a major transcription factor in islet cells determining β-cell survival and function, resulting in increased expression of genes involved with insulin secretion (Abcc8, Kcnj11, Slc2a2, Cacn1c) together with the genes encoding the incretin receptors Glp1r and Gipr. In addition, the elevated expression of insulin signalling genes (Slc2a4, Insr, Irs1, Akt1, Pik3ca, Ppm1b) in skeletal muscle associated with the db/db phenotype was downregulated by peptide treatment These data suggest that the anti-diabetic properties of [A14K]PGLa-AM1 are mediated by molecular changes that enhance both the secretion and action of insulin.
Collapse
Affiliation(s)
- Vishal Musale
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK
| | - R Charlotte Moffett
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK
| | - J Michael Conlon
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK.
| | - Peter R Flatt
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK
| | - Yasser H Abdel-Wahab
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK
| |
Collapse
|
|
24
|
Mazzotta C, Basu S, Gower AC, Karki S, Farb MG, Sroczynski E, Zizza E, Sarhan A, Pande AN, Walsh K, Dobrilovic N, Gokce N. Perivascular Adipose Tissue Inflammation in Ischemic Heart Disease. Arterioscler Thromb Vasc Biol 2021; 41:1239-1250. [PMID: 33504180 DOI: 10.1161/atvbaha.120.315865] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE There is growing recognition that adipose tissue-derived proatherogenic mediators contribute to obesity-related cardiovascular disease. We sought to characterize regional differences in perivascular adipose tissue (PVAT) phenotype in relation to atherosclerosis susceptibility. Approach and Results: We examined thoracic PVAT samples in 34 subjects (body mass index 32±6 kg/m2, age 59±11 years) undergoing valvular, aortic, or coronary artery bypass graft surgeries and performed transcriptomic characterization using whole-genome expression profiling and quantitative polymerase chain reaction analyses. We identified a highly inflamed region of PVAT surrounding the human aortic root in close proximity to coronary takeoff and adjoining epicardial fat. In subjects undergoing coronary artery bypass graft, we found 300 genes significantly upregulated (false discovery rate Q<0.1) in paired samples of PVAT surrounding the aortic root compared with nonatherosclerotic left internal mammary artery. Genes encoding proteins mechanistically implicated in atherogenesis were enriched in aortic PVAT consisting of signaling pathways linked to inflammation, WNT (wingless-related integration site) signaling, matrix remodeling, coagulation, and angiogenesis. Overexpression of several proatherogenic transcripts, including IL1β, CCL2 (MCP-1), and IL6, were confirmed by quantitative polymerase chain reaction and significantly bolstered in coronary artery disease subjects. Angiographic coronary artery disease burden quantified by the Gensini score positively correlated with the expression of inflammatory genes in PVAT. Moreover, periaortic adipose inflammation was markedly higher in obese subjects with striking upregulation (≈8-fold) of IL1β expression compared to nonobese individuals. CONCLUSIONS Proatherogenic mediators that originate from dysfunctional PVAT may contribute to vascular disease mechanisms in human vessels. Moreover, PVAT may adopt detrimental properties under obese conditions that play a key role in the pathophysiology of ischemic heart disease. Graphic Abstract: A graphic abstract is available for this article.
Collapse
Affiliation(s)
- Celestina Mazzotta
- Evans Department of Medicine and Whitaker Cardiovascular Institute (C.M., S.B., S.K., M.G.F., E.S., E.Z., A.S., A.N.P., N.G.), Boston University School of Medicine, MA
| | - Sanchita Basu
- Evans Department of Medicine and Whitaker Cardiovascular Institute (C.M., S.B., S.K., M.G.F., E.S., E.Z., A.S., A.N.P., N.G.), Boston University School of Medicine, MA
| | - Adam C Gower
- Clinical and Translational Science Institute (A.C.G.), Boston University School of Medicine, MA
| | | | - Melissa G Farb
- Evans Department of Medicine and Whitaker Cardiovascular Institute (C.M., S.B., S.K., M.G.F., E.S., E.Z., A.S., A.N.P., N.G.), Boston University School of Medicine, MA
| | - Emily Sroczynski
- Evans Department of Medicine and Whitaker Cardiovascular Institute (C.M., S.B., S.K., M.G.F., E.S., E.Z., A.S., A.N.P., N.G.), Boston University School of Medicine, MA
| | - Elaina Zizza
- Evans Department of Medicine and Whitaker Cardiovascular Institute (C.M., S.B., S.K., M.G.F., E.S., E.Z., A.S., A.N.P., N.G.), Boston University School of Medicine, MA
| | - Anas Sarhan
- Evans Department of Medicine and Whitaker Cardiovascular Institute (C.M., S.B., S.K., M.G.F., E.S., E.Z., A.S., A.N.P., N.G.), Boston University School of Medicine, MA
| | - Ashvin N Pande
- Evans Department of Medicine and Whitaker Cardiovascular Institute (C.M., S.B., S.K., M.G.F., E.S., E.Z., A.S., A.N.P., N.G.), Boston University School of Medicine, MA
| | - Kenneth Walsh
- Hematovascular Biology Center and the Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville (K.W.)
| | - Nikola Dobrilovic
- Division of Cardiac Surgery, Department of Surgery, Boston Medical Center, MA (N.D.)
| | - Noyan Gokce
- Evans Department of Medicine and Whitaker Cardiovascular Institute (C.M., S.B., S.K., M.G.F., E.S., E.Z., A.S., A.N.P., N.G.), Boston University School of Medicine, MA
| |
Collapse
|
|
25
|
Lin Y, Ding S, Chen Y, Xiang M, Xie Y. Cardiac Adipose Tissue Contributes to Cardiac Repair: a Review. Stem Cell Rev Rep 2021; 17:1137-1153. [PMID: 33389679 DOI: 10.1007/s12015-020-10097-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2020] [Indexed: 02/06/2023]
Abstract
Cardiac adipose tissue is a metabolically active adipose tissue in close proximity to heart. Recent studies emphasized the benefits of cardiac adipose tissue in heart remodeling, such as reducing infarction size, enhancing neovascularization and regulating immune response, through a series of cellular mechanisms. In the present manuscript, we provide a comprehensive review regarding the role of cardiac adipose tissue in cardiac repair. We focus on different cardiac adipose tissues according to their distinguished anatomical structures. This review summarizes the latest evidence on the relationship between cardiac adipose tissue and cardiac repair. Cardiac adipose tissues (CAT) were systematically reviewed in the current manuscript which focused on the components of CAT, debates about cardiac adipose stem cells and their effect on heart.
Collapse
Affiliation(s)
- Yan Lin
- Department of Cardiology, Cardiovascular Key Laboratory of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China
| | - Siyin Ding
- Department of Cardiology, Cardiovascular Key Laboratory of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China
| | - Yuwen Chen
- Department of Cardiology, Cardiovascular Key Laboratory of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China
| | - Meixiang Xiang
- Department of Cardiology, Cardiovascular Key Laboratory of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.
| | - Yao Xie
- Department of Cardiology, Cardiovascular Key Laboratory of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.
| |
Collapse
|
|
26
|
Chen Y, Qin Z, Wang Y, Li X, Zheng Y, Liu Y. Role of Inflammation in Vascular Disease-Related Perivascular Adipose Tissue Dysfunction. Front Endocrinol (Lausanne) 2021; 12:710842. [PMID: 34456867 PMCID: PMC8385491 DOI: 10.3389/fendo.2021.710842] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022] Open
Abstract
Perivascular adipose tissue (PVAT) is the connective tissue around most blood vessels throughout the body. It provides mechanical support and maintains vascular homeostasis in a paracrine/endocrine manner. Under physiological conditions, PVAT has anti-inflammatory effects, improves free fatty acid metabolism, and regulates vasodilation. In pathological conditions, PVAT is dysfunctional, secretes many anti-vasodilator factors, and participates in vascular inflammation through various cells and mediators; thus, it causes dysfunction involving vascular smooth muscle cells and endothelial cells. Inflammation is an important pathophysiological event in many vascular diseases, such as vascular aging, atherosclerosis, and hypertension. Therefore, the pro-inflammatory crosstalk between PVAT and blood vessels may comprise a novel therapeutic target for the prevention and treatment of vascular diseases. In this review, we summarize findings concerning PVAT function and inflammation in different pathophysiological backgrounds, focusing on the secretory functions of PVAT and the crosstalk between PVAT and vascular inflammation in terms of vascular aging, atherosclerosis, hypertension, diabetes mellitus, and other diseases. We also discuss anti-inflammatory treatment for potential vascular diseases involving PVAT.
Collapse
Affiliation(s)
- Yaozhi Chen
- Center for Cardiovascular Medicine, First Hospital of Jilin University, Changchun, China
| | - Zeyu Qin
- Department of Respiratory Medicine, First Hospital of Jilin University, Changchun, China
| | - Yaqiong Wang
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, China
| | - Xin Li
- Center for Cardiovascular Medicine, First Hospital of Jilin University, Changchun, China
| | - Yang Zheng
- Center for Cardiovascular Medicine, First Hospital of Jilin University, Changchun, China
- *Correspondence: Yunxia Liu, ; Yang Zheng,
| | - Yunxia Liu
- Center for Cardiovascular Medicine, First Hospital of Jilin University, Changchun, China
- *Correspondence: Yunxia Liu, ; Yang Zheng,
| |
Collapse
|
|
27
|
Scheja L, Heeren J. Novel Adipose Tissue Targets to Prevent and Treat Atherosclerosis. Handb Exp Pharmacol 2020; 270:289-310. [PMID: 33373032 DOI: 10.1007/164_2020_363] [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] [Indexed: 02/07/2023]
Abstract
Adipose tissue as a major organ of lipid and lipoprotein metabolism has a major impact on metabolic homeostasis and thus influences the development of atherosclerosis and related cardiometabolic diseases. Unhealthy adipose tissue, which is often associated with obesity and systemic insulin resistance, promotes the development of diabetic dyslipidemia and can negatively affect vascular tissue homeostasis by secreting pro-inflammatory peptides and lipids. Conversely, paracrine and endocrine factors that are released from healthy adipose tissue can preserve metabolic balance and a functional vasculature. In this chapter, we describe adipose tissue types relevant for atherosclerosis and address the question how lipid metabolism as well as regulatory molecules produced in these fat depots can be targeted to counteract atherogenic processes in the vessel wall and improve plasma lipids. We discuss the role of adipose tissues in the action of approved drugs with anti-atherogenic activity. In addition, we present potential novel targets and therapeutic approaches aimed at increasing lipoprotein disposal in adipose tissue, boosting the activity of heat-producing (thermogenic) adipocytes, reducing adipose tissue inflammation, and improving or replacing beneficial hormones released from adipose tissues. Furthermore, we describe the future potential of innovative drug delivery technologies.
Collapse
Affiliation(s)
- Ludger Scheja
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Joerg Heeren
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
|
28
|
Queiroz M, Sena CM. Perivascular adipose tissue in age-related vascular disease. Ageing Res Rev 2020; 59:101040. [PMID: 32112889 DOI: 10.1016/j.arr.2020.101040] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 01/31/2020] [Accepted: 02/23/2020] [Indexed: 12/16/2022]
Abstract
Perivascular adipose tissue (PVAT), a crucial regulator of vascular homeostasis, is actively involved in vascular dysfunction during aging. PVAT releases various adipocytokines, chemokines and growth factors. In an endocrine and paracrine manner PVAT-derived factors regulate vascular signalling and inflammation modulating functions of adjacent layers of the vasculature. Pathophysiological conditions such as obesity, type 2 diabetes, vascular injury and aging can cause PVAT dysfunction, leading to vascular endothelial and smooth muscle cell dysfunctions. We and others have suggested that PVAT is involved in the inflammatory response of the vascular wall in diet induced obesity animal models leading to vascular dysfunction due to disappearance of the physiological anticontractile effect. Previous studies confirm a crucial role for pinpointed PVAT inflammation in promoting vascular oxidative stress and inflammation in aging, enhancing the risk for development of cardiovascular disease. In this review, we discuss several studies and mechanisms linking PVAT to age-related vascular diseases. An overview of the suggested roles played by PVAT in different disorders associated with the vasculature such as endothelial dysfunction, neointimal formation, aneurysm, vascular contractility and stiffness will be performed. PVAT may be considered a potential target for therapeutic intervention in age-related vascular disease.
Collapse
Affiliation(s)
- Marcelo Queiroz
- Institute of Physiology, iCBR, Faculty of Medicine, University of Coimbra, Portugal
| | - Cristina M Sena
- Institute of Physiology, iCBR, Faculty of Medicine, University of Coimbra, Portugal.
| |
Collapse
|
|
29
|
Abstract
The perivascular adipose tissue (PVAT) has been recently recognized as an important factor in vascular biology, with implications in the pathogenesis of cardiovascular diseases. The cell types and the precursor cells of PVAT appear to be different according to their location, with the component cell type including white, brown, and beige adipocytes. PVAT releases a panel of adipokines and cytokines that maintain vascular homeostasis, but it also has the ability of intervention in the pathogenesis of the atherosclerotic plaques development and in the vascular tone modulation. In this review, we summarize the current knowledge and discuss the role of PVAT as a major contributing factor in the pathogenesis of ischemic coronary disease, hypertension, obesity, and diabetes mellitus. The new perspective of PVAT as an endocrine organ, along with the recent knowledge of the mechanisms involved in dysfunctional PVAT intervention in local vascular homeostasis perturbations, nowadays represent a new area of research in cardiovascular pathology, aiming to discover new therapeutic methods.
Collapse
|
|
30
|
Turaihi AH, Serné EH, Molthoff CFM, Koning JJ, Knol J, Niessen HW, Goumans MJTH, van Poelgeest EM, Yudkin JS, Smulders YM, Jimenez CR, van Hinsbergh VWM, Eringa EC. Perivascular Adipose Tissue Controls Insulin-Stimulated Perfusion, Mitochondrial Protein Expression, and Glucose Uptake in Muscle Through Adipomuscular Arterioles. Diabetes 2020; 69:603-613. [PMID: 32005705 DOI: 10.2337/db18-1066] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 01/24/2020] [Indexed: 11/13/2022]
Abstract
Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls vascular function through outside-to-inside communication and through vessel-to-vessel, or "vasocrine," signaling. However, direct experimental evidence supporting a role of local PVAT in regulating IMVR and insulin sensitivity in vivo is lacking. Here, we studied muscles with and without PVAT in mice using combined contrast-enhanced ultrasonography and intravital microscopy to measure IMVR and gracilis artery diameter at baseline and during the hyperinsulinemic-euglycemic clamp. We show, using microsurgical removal of PVAT from the muscle microcirculation, that local PVAT depots regulate insulin-stimulated muscle perfusion and glucose uptake in vivo. We discovered direct microvascular connections between PVAT and the distal muscle microcirculation, or adipomuscular arterioles, the removal of which abolished IMVR. Local removal of intramuscular PVAT altered protein clusters in the connected muscle, including upregulation of a cluster featuring Hsp90ab1 and Hsp70 and downregulation of a cluster of mitochondrial protein components of complexes III, IV, and V. These data highlight the importance of PVAT in vascular and metabolic physiology and are likely relevant for obesity and diabetes.
Collapse
Affiliation(s)
- Alexander H Turaihi
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Erik H Serné
- Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Carla F M Molthoff
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Jasper J Koning
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Jaco Knol
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Hans W Niessen
- Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Marie Jose T H Goumans
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Erik M van Poelgeest
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - John S Yudkin
- Institute of Cardiovascular Science, Division of Medicine, University College London, London, U.K
| | - Yvo M Smulders
- Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Connie R Jimenez
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Victor W M van Hinsbergh
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Etto C Eringa
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands
| |
Collapse
|
|
31
|
Rotondo F, Ho-Palma AC, Romero MDM, Remesar X, Fernández-López JA, Alemany M. Higher lactate production from glucose in cultured adipose nucleated stromal cells than for rat adipocytes. Adipocyte 2019; 8:61-76. [PMID: 30676233 PMCID: PMC6768231 DOI: 10.1080/21623945.2019.1569448] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
White adipose tissue (WAT) nucleated stromal cells (NSC) play important roles in regulation, defense, regeneration and metabolic control. In WAT sites, the proportions and functions of NSC change under diverse physiological or pathologic conditions. We had previously observed the massive anaerobic wasting of glucose to lactate and glycerol in rat epididymal adipocytes. To test site variability, and whether the adipocyte extensive anaerobic metabolism of glucose was found in NSC, we analyzed, in parallel, subcutaneous, mesenteric and epididymal WAT of male adult Wistar rats. Adipocytes and NSC fractions, were isolated, counted and incubated (as well as red blood cells: RBC) with glucose, and their ability to use glucose and produce lactate, glycerol, and free fatty acids was measured. Results were computed taking into account the number of cells present in WAT samples. Cell numbers were found in proportions close to 1:13:100 (respectively, for adipocytes, NSC and RBC) but their volumes followed a reversed pattern: 7,500:10:1. When counting only non-fat cell volumes, the ratios changed dramatically to 100:10:1. RBC contribution to lactate production was practically insignificant. In most samples, NSC produced more lactate than adipocytes did, but only adipocytes secreted glycerol (and fatty acids in smaller amounts). Glucose consumption was also highest in NSC, especially in mesenteric WAT. The heterogeneous NSC showed a practically anaerobic metabolism (like that already observed in adipocytes). Thus, NSC quantitative production of lactate markedly contributed (i.e. more than adipocytes) to WAT global use (wasting) of glucose. We also confirmed that glucose-derived glycerol is exclusively produced by adipocytes.
Collapse
Affiliation(s)
- Floriana Rotondo
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
| | - Ana-Cecilia Ho-Palma
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
| | - María del Mar Romero
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
- Institute of Biomedicine, University of Barcelona, Barcelona, Spain
- CIBER-OBN Research Web, Barcelona, Spain
| | - Xavier Remesar
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
- Institute of Biomedicine, University of Barcelona, Barcelona, Spain
- CIBER-OBN Research Web, Barcelona, Spain
| | - José Antonio Fernández-López
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
- Institute of Biomedicine, University of Barcelona, Barcelona, Spain
- CIBER-OBN Research Web, Barcelona, Spain
| | - Marià Alemany
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
- Institute of Biomedicine, University of Barcelona, Barcelona, Spain
- CIBER-OBN Research Web, Barcelona, Spain
| |
Collapse
|
|
32
|
Chen H, Vanhoutte PM, Leung SWS. Vascular adenosine monophosphate-activated protein kinase: Enhancer, brake or both? Basic Clin Pharmacol Toxicol 2019; 127:81-91. [PMID: 31671245 DOI: 10.1111/bcpt.13357] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 10/24/2019] [Indexed: 12/25/2022]
Abstract
Adenosine monophosphate-activated protein kinase (AMPK), expressed/present ubiquitously in the body, contributes to metabolic regulation. In the vasculature, activation of AMPK is associated with several beneficial biological effects including enhancement of vasodilatation, reduction of oxidative stress and inhibition of inflammatory reactions. The vascular protective effects of certain anti-diabetic (metformin and sitagliptin) or lipid-lowering (simvastatin and fenofibrate) therapeutic agents, of active components of Chinese medicinal herbs (resveratrol and berberine) and of pharmacological agents (AICAR, A769662 and PT1) have been attributed to the activation of AMPK (in endothelial cells, vascular smooth muscle cells and/or perivascular adipocytes), independently of changes in the metabolic profile (eg glucose tolerance and/or plasma lipoprotein levels), leading to improved endothelium-derived nitric oxide-mediated vasodilatation and attenuated endothelium-derived cyclooxygenase-dependent vasoconstriction. By contrast, endothelial AMPK activation with pharmacological agents or by genetic modification is associated with reduced endothelium-dependent relaxations in small blood vessels and elevated systolic blood pressure. Indeed, AMPK activators inhibit endothelium-dependent hyperpolarization (EDH)-type relaxations in superior mesenteric arteries, partly by inhibiting endothelial calcium-activated potassium channel signalling. Therefore, AMPK activation is not necessarily beneficial in terms of endothelial function. The contribution of endothelial AMPK in the regulation of vascular tone, in particular in the microvasculature where EDH plays a more important role, remains to be characterized.
Collapse
Affiliation(s)
- Hui Chen
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Paul Michel Vanhoutte
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Susan Wai Sum Leung
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
33
|
Saxton SN, Clark BJ, Withers SB, Eringa EC, Heagerty AM. Mechanistic Links Between Obesity, Diabetes, and Blood Pressure: Role of Perivascular Adipose Tissue. Physiol Rev 2019; 99:1701-1763. [PMID: 31339053 DOI: 10.1152/physrev.00034.2018] [Citation(s) in RCA: 163] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore the potential for manipulating adipose tissue morphology and its immune cell population to improve cardiovascular health in obesity.
Collapse
Affiliation(s)
- Sophie N Saxton
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Ben J Clark
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Sarah B Withers
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Etto C Eringa
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Anthony M Heagerty
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| |
Collapse
|
|
34
|
Abstract
Our understanding of the role of the vascular endothelium has evolved over the past 2 decades, with the recognition that it is a dynamically regulated organ and that it plays a nodal role in a variety of physiological and pathological processes. Endothelial cells (ECs) are not only a barrier between the circulation and peripheral tissues, but also actively regulate vascular tone, blood flow, and platelet function. Dysregulation of ECs contributes to pathological conditions such as vascular inflammation, atherosclerosis, hypertension, cardiomyopathy, retinopathy, neuropathy, and cancer. The close anatomic relationship between vascular endothelium and highly vascularized metabolic organs/tissues suggests that the crosstalk between ECs and these organs is vital for both vascular and metabolic homeostasis. Numerous reports support that hyperlipidemia, hyperglycemia, and other metabolic stresses result in endothelial dysfunction and vascular complications. However, how ECs may regulate metabolic homeostasis remains poorly understood. Emerging data suggest that the vascular endothelium plays an unexpected role in the regulation of metabolic homeostasis and that endothelial dysregulation directly contributes to the development of metabolic disorders. Here, we review recent studies about the pivotal role of ECs in glucose and lipid homeostasis. In particular, we introduce the concept that the endothelium adjusts its barrier function to control the transendothelial transport of fatty acids, lipoproteins, LPLs (lipoprotein lipases), glucose, and insulin. In addition, we summarize reports that ECs communicate with metabolic cells through EC-secreted factors and we discuss how endothelial dysregulation contributes directly to the development of obesity, insulin resistance, dyslipidemia, diabetes mellitus, cognitive defects, and fatty liver disease.
Collapse
Affiliation(s)
- Xinchun Pi
- From the Section of Athero & Lipo, Department of Medicine, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P., L.X.)
| | - Liang Xie
- From the Section of Athero & Lipo, Department of Medicine, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P., L.X.)
| | - Cam Patterson
- University of Arkansas for Medical Sciences, Little Rock (C.P.)
| |
Collapse
|
|
35
|
Saxton SN, Withers SB, Nyvad J, Mazur A, Matchkov V, Heagerty AM, Aalkjær C. Perivascular Adipose Tissue Contributes to the Modulation of Vascular Tone in vivo. J Vasc Res 2019; 56:320-332. [PMID: 31550717 DOI: 10.1159/000502689] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 08/13/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte β3-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. OBJECTIVE We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of β3-adrenoceptors and adiponectin. METHOD In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). RESULTS We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using β3-adrenoceptor inhibition, and activation of β3-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The β3-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon β3-adrenoceptor activation. CONCLUSIONS These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte β3-adrenoceptors, which may trigger release of the vasodilator adiponectin.
Collapse
Affiliation(s)
- Sophie N Saxton
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
| | - Sarah B Withers
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom.,School of Environment and Life Sciences, University of Salford, Salford, United Kingdom
| | - Jakob Nyvad
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | | | | | - Anthony M Heagerty
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
| | - Christian Aalkjær
- Department of Biomedicine, Aarhus University, Aarhus, Denmark, .,Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark,
| |
Collapse
|
|
36
|
Meijer RI, Hoevenaars FPM, Serné EH, Yudkin JS, Kokhuis TJA, Weijers EM, van Hinsbergh VWM, Smulders YM, Eringa EC. JNK2 in myeloid cells impairs insulin's vasodilator effects in muscle during early obesity development through perivascular adipose tissue dysfunction. Am J Physiol Heart Circ Physiol 2019; 317:H364-H374. [PMID: 31149833 DOI: 10.1152/ajpheart.00663.2018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Reduced vasodilator properties of insulin in obesity are caused by changes in perivascular adipose tissue and contribute to microvascular dysfunction in skeletal muscle. The causes of this dysfunction are unknown. The effects of a short-term Western diet on JNK2-expressing cells in perivascular adipose tissue (PVAT) on insulin-induced vasodilation and perfusion of skeletal muscle were assessed. In vivo, 2 wk of Western diet (WD) reduced whole body insulin sensitivity and insulin-stimulated muscle perfusion, determined using contrast ultrasonography during the hyperinsulinemic clamp. Ex vivo, WD triggered accumulation of PVAT in skeletal muscle and blunted its ability to facilitate insulin-induced vasodilation. Labeling of myeloid cells with green fluorescent protein identified bone marrow as a source of PVAT in muscle. To study whether JNK2-expressing inflammatory cells from bone marrow were involved, we transplanted JNK2-/- bone marrow to WT mice. Deletion of JNK2 in bone marrow rescued the vasodilator phenotype of PVAT during WD exposure. JNK2 deletion in myeloid cells prevented the WD-induced increase in F4/80 expression. Even though WD and JNK2 deletion resulted in specific changes in gene expression of PVAT; epididymal and subcutaneous adipose tissue; expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, or protein inhibitor of STAT1 was not affected. In conclusion, short-term Western diet triggers infiltration of JNK2-positive myeloid cells into PVAT, resulting in PVAT dysfunction, nonclassical inflammation, and loss of insulin-induced vasodilatation in vivo and ex vivo.NEW & NOTEWORTHY We demonstrate that in the earliest phase of weight gain, changes in perivascular adipose tissue in muscle impair insulin-stimulated muscle perfusion. The hallmark of these changes is infiltration by inflammatory cells. Deletion of JNK2 from the bone marrow restores the function of perivascular adipose tissue to enhance insulin's vasodilator effects in muscle, showing that the bone marrow contributes to regulation of muscle perfusion.
Collapse
Affiliation(s)
- Rick I Meijer
- Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands
| | - Femke P M Hoevenaars
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands
| | - Erik H Serné
- Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands
| | - John S Yudkin
- Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands.,Department of Medicine, University College London, London, United Kingdom
| | - Tom J A Kokhuis
- Biomedical Engineering, Thorax Center, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ester M Weijers
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands
| | - Victor W M van Hinsbergh
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands
| | - Yvo M Smulders
- Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands
| | - Etto C Eringa
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands
| |
Collapse
|
|
37
|
Koliaki C, Liatis S, Kokkinos A. Obesity and cardiovascular disease: revisiting an old relationship. Metabolism 2019; 92:98-107. [PMID: 30399375 DOI: 10.1016/j.metabol.2018.10.011] [Citation(s) in RCA: 421] [Impact Index Per Article: 70.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/22/2018] [Accepted: 10/25/2018] [Indexed: 02/06/2023]
Abstract
A wealth of clinical and epidemiological evidence has linked obesity to a broad spectrum of cardiovascular diseases (CVD) including coronary heart disease, heart failure, hypertension, stroke, atrial fibrillation and sudden cardiac death. Obesity can increase CVD morbidity and mortality directly and indirectly. Direct effects are mediated by obesity-induced structural and functional adaptations of the cardiovascular system to accommodate excess body weight, as well as by adipokine effects on inflammation and vascular homeostasis. Indirect effects are mediated by co-existing CVD risk factors such as insulin resistance, hyperglycemia, hypertension and dyslipidemia. Adipose tissue (AT) quality and functionality are more relevant aspects for cardiometabolic risk than its total amount. The consequences of maladaptive AT expansion in obesity are local and systemic: the local include inflammation, hypoxia, dysregulated adipokine secretion and impaired mitochondrial function; the systemic comprise insulin resistance, abnormal glucose/lipid metabolism, hypertension, a pro-inflammatory and pro-thrombotic state and endothelial dysfunction, all of which provide linking mechanisms for the association between obesity and CVD. The present narrative review summarizes the major pathophysiological links between obesity and CVD (traditional and novel concepts), analyses the heterogeneity of obesity-related cardiometabolic consequences, and provides an overview of the cardiovascular impact of weight loss interventions.
Collapse
Affiliation(s)
- Chrysi Koliaki
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Stavros Liatis
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.
| |
Collapse
|
|
38
|
Muscle Insulin Resistance and the Inflamed Microvasculature: Fire from Within. Int J Mol Sci 2019; 20:ijms20030562. [PMID: 30699907 PMCID: PMC6387226 DOI: 10.3390/ijms20030562] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 01/21/2019] [Accepted: 01/22/2019] [Indexed: 12/18/2022] Open
Abstract
Insulin is a vascular hormone and regulates vascular tone and reactivity. Muscle is a major insulin target that is responsible for the majority of insulin-stimulated glucose use. Evidence confirms that muscle microvasculature is an important insulin action site and critically regulates insulin delivery to muscle and action on myocytes, thereby affecting insulin-mediated glucose disposal. Insulin via activation of its signaling cascade in the endothelial cells increases muscle microvascular perfusion, which leads to an expansion of the endothelial exchange surface area. Insulin’s microvascular actions closely couple with its metabolic actions in muscle and blockade of insulin-mediated microvascular perfusion reduces insulin-stimulated muscle glucose disposal. Type 2 diabetes is associated with chronic low-grade inflammation, which engenders both metabolic and microvascular insulin resistance through endocrine, autocrine and paracrine actions of multiple pro-inflammatory factors. Here, we review the crucial role of muscle microvasculature in the regulation of insulin action in muscle and how inflammation in the muscle microvasculature affects insulin’s microvascular actions as well as metabolic actions. We propose that microvascular insulin resistance induced by inflammation is an early event in the development of metabolic insulin resistance and eventually type 2 diabetes and its related cardiovascular complications, and thus is a potential therapeutic target for the prevention or treatment of obesity and diabetes.
Collapse
|
|
39
|
Akoumianakis I, Antoniades C. Impaired Vascular Redox Signaling in the Vascular Complications of Obesity and Diabetes Mellitus. Antioxid Redox Signal 2019; 30:333-353. [PMID: 29084432 DOI: 10.1089/ars.2017.7421] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: Oxidative stress, a crucial regulator of vascular disease pathogenesis, may be involved in the vascular complications of obesity, systemic insulin resistance (IR), and diabetes mellitus (DM). Recent Advances: Excessive production of reactive oxygen species in the vascular wall has been linked with vascular disease pathogenesis. Recent evidence has revealed that vascular redox state is dysregulated in cases of obesity, systemic IR, and DM, potentially participating in the well-known vascular complications of these disease entities. Critical Issues: The detrimental effects of obesity and the metabolic syndrome on vascular biology have been extensively described at a clinical level. Further, vascular oxidative stress has often been associated with the presence of obesity and IR as well as with a variety of detrimental vascular phenotypes. However, the mechanisms of vascular redox state regulation under conditions of obesity and systemic IR, as well as their clinical relevance, are not adequately explored. In addition, the notion of vascular IR, and its relationship with systemic parameters of obesity and systemic IR, is not fully understood. In this review, we present all the important components of vascular redox state and the evidence linking oxidative stress with obesity and IR. Future Directions: Future studies are required to describe the cellular effects and the translational potential of vascular redox state in the context of vascular disease. In addition, further elucidation of the direct vascular effects of obesity and IR is required for better management of the vascular complications of DM.
Collapse
Affiliation(s)
- Ioannis Akoumianakis
- Division of Cardiovascular Medicine, University of Oxford , Oxford, United Kingdom
| | | |
Collapse
|
|
40
|
Stehouwer CDA. Microvascular Dysfunction and Hyperglycemia: A Vicious Cycle With Widespread Consequences. Diabetes 2018; 67:1729-1741. [PMID: 30135134 DOI: 10.2337/dbi17-0044] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 06/18/2018] [Indexed: 11/13/2022]
Abstract
Microvascular and metabolic physiology are tightly linked. This Perspective reviews evidence that 1) the relationship between hyperglycemia and microvascular dysfunction (MVD) is bidirectional and constitutes a vicious cycle; 2) MVD in diabetes affects many, if not all, organs, which may play a role in diabetes-associated comorbidities such as depression and cognitive impairment; and 3) MVD precedes, and contributes to, hyperglycemia in type 2 diabetes (T2D) through impairment of insulin-mediated glucose disposal and, possibly, insulin secretion. Obesity and adverse early-life exposures are important drivers of MVD. MVD can be improved through weight loss (in obesity) and through exercise. Pharmacological interventions to improve MVD are an active area of investigation.
Collapse
Affiliation(s)
- Coen D A Stehouwer
- Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre+, Maastricht, the Netherlands
| |
Collapse
|
|
41
|
Dias-Neto M, Meekel JP, van Schaik TG, Hoozemans J, Sousa-Nunes F, Henriques-Coelho T, Lely RJ, Wisselink W, Blankensteijn JD, Yeung KK. High Density of Periaortic Adipose Tissue in Abdominal Aortic Aneurysm. Eur J Vasc Endovasc Surg 2018; 56:663-671. [PMID: 30115505 DOI: 10.1016/j.ejvs.2018.07.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 07/06/2018] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Perivascular adipose tissue (PVAT) is currently seen as a paracrine organ that produces vasoactive substances, including inflammatory agents, which may have an impact on the vasculature. In this study PVAT density was quantified in patients with an aortic aneurysm and compared with those with a non-dilated aorta. Since chronic inflammation, as the pathway to medial thinning, is a hallmark of abdominal aortic aneurysms (AAAs), it was hypothesised that PVAT density is higher in AAA patients. METHODS In this multicentre retrospective case control study, three groups of patients were included: non-treated asymptomatic AAA (n = 140), aortoiliac occlusive disease (AIOD) (n = 104), and individuals without aortic pathology (n = 97). A Hounsfield units based analysis was performed by computed tomography (CT). As a proxy for PVAT, the density of adipose tissue 10 mm circumferential to the infrarenal aorta was analysed in each consecutive CT slice. Intra-individual PVAT differences were reported as the difference in PVAT density between the region of the maximum AAA diameter (or the mid-aortic region in patients with AIOD or controls) and the two uppermost slices of infrarenal non-dilated aorta just below the renal arteries. Furthermore, subcutaneous (SAT) and visceral (VAT) adipose tissue measurements were performed. Linear models were fitted to assess the association between the study groups, different adipose tissue compartments, and between adipose tissue compartments and aortic dimensions. RESULTS AAA patients presented higher intra-individual PVAT differences, with higher PVAT density around the aneurysm sac than the healthy neck. This association persisted after adjustment for cardiovascular risk factors and diseases and other fat compartments (β = 13.175, SE 4.732, p = .006). Furthermore, intra-individual PVAT differences presented the highest correlation with aortic volume that persisted after adjustment for other fat compartments, body mass index, sex, and age (β = 0.566, 0.200, p = .005). CONCLUSION The results suggest a relation between the deposition of PVAT and AAA pathophysiology. Further research should explore the exact underlying processes.
Collapse
Affiliation(s)
- Marina Dias-Neto
- Department of Angiology and Vascular Surgery, São João Hospital Centre, Porto, Portugal; Cardiovascular Research Unit, Faculty of Medicine, University of Porto, Portugal
| | - Jorn P Meekel
- Department of Vascular Surgery, VU University Medical Centre, Amsterdam, The Netherlands; Department of Physiology (Amsterdam Cardiovascular Sciences) VU University Medical Centre, Amsterdam, The Netherlands
| | - Theodorus G van Schaik
- Department of Vascular Surgery, VU University Medical Centre, Amsterdam, The Netherlands; Department of Physiology (Amsterdam Cardiovascular Sciences) VU University Medical Centre, Amsterdam, The Netherlands
| | - Jacqueline Hoozemans
- Department of Physiology (Amsterdam Cardiovascular Sciences) VU University Medical Centre, Amsterdam, The Netherlands
| | - Fábio Sousa-Nunes
- Cardiovascular Research Unit, Faculty of Medicine, University of Porto, Portugal
| | | | - Rutger J Lely
- Department of Interventional Radiology, VU University Medical Centre, Amsterdam, The Netherlands
| | - Willem Wisselink
- Department of Vascular Surgery, VU University Medical Centre, Amsterdam, The Netherlands
| | - Jan D Blankensteijn
- Department of Vascular Surgery, VU University Medical Centre, Amsterdam, The Netherlands
| | - Kak K Yeung
- Department of Vascular Surgery, VU University Medical Centre, Amsterdam, The Netherlands; Department of Physiology (Amsterdam Cardiovascular Sciences) VU University Medical Centre, Amsterdam, The Netherlands.
| |
Collapse
|
|
42
|
Qiu T, Li M, Tanner MA, Yang Y, Sowers JR, Korthuis RJ, Hill MA. Depletion of dendritic cells in perivascular adipose tissue improves arterial relaxation responses in type 2 diabetic mice. Metabolism 2018; 85:76-89. [PMID: 29530798 PMCID: PMC6062442 DOI: 10.1016/j.metabol.2018.03.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 02/19/2018] [Accepted: 03/02/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Accumulation of multiple subtypes of immune cells in perivascular adipose tissue (PVAT) has been proposed to cause vascular inflammation and dysfunction in type 2 diabetes (T2DM). This study was designed to investigate specific roles for dendritic cells in PVAT in the development of vascular inflammation and impaired PVAT-mediated vasorelaxation in T2DM. METHODS AND RESULTS Studies were performed using db/db mice (model of T2DM) and their Db heterozygote (DbHET), lean and normoglycemic controls. Dendritic cell depletion was performed by cross-breeding DbHet with Flt3l-/- (null for ligand for FMS-kinase tyrosine kinase) mice. Using PCR, it was found that the majority of dendritic cells (CD11c+) were located in PVAT rather than the vascular wall. Flow cytometry similarly showed greater dendritic cell accumulation in adipose tissue from db/db mice than DbHET controls. Adipose tissue from db/db mice displayed increased mRNA levels of proinflammatory cytokines TNF-α and IL-6 and decreased mRNA levels of the anti-inflammatory mediator adiponectin, compared to DbHET mice. Depletion of dendritic cells in dbFlt3l-/dbFlt3l- (confirmed by flow cytometry) reduced TNF-α and IL-6 mRNA levels in diabetic adipose tissue without influencing adiponection expression. Moreover, in mesenteric arteries, dendritic cell depletion improved the ability of PVAT to augment acetylcholine-induced vasorelaxation and anti-contractile activity. CONCLUSIONS In a murine model of T2DM, dendritic cells accumulated predominantly in PVAT, as opposed to the vessel wall, per se. Accumulation of dendritic cells in PVAT was associated with overproduction of pro-inflammatory cytokines, which contributed to an impaired ability of PVAT to augment vasorelaxation and exert anti-contractile activity in T2DM.
Collapse
Affiliation(s)
- Tianyi Qiu
- Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA; Department of Medical Pharmacology and Physiology, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA
| | - Min Li
- Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA
| | - Miles A Tanner
- Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA
| | - Yan Yang
- Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA
| | - James R Sowers
- Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA; Department of Medical Pharmacology and Physiology, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA
| | - Ronald J Korthuis
- Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA; Department of Medical Pharmacology and Physiology, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA
| | - Michael A Hill
- Dalton Cardiovascular Research Center, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA; Department of Medical Pharmacology and Physiology, University of Missouri and Truman VA Medical Center, Columbia, MO 65211, USA.
| |
Collapse
|
|
43
|
Verkaik M, Juni RP, van Loon EPM, van Poelgeest EM, Kwekkeboom RFJ, Gam Z, Richards WG, Ter Wee PM, Hoenderop JG, Eringa EC, Vervloet MG. FGF23 impairs peripheral microvascular function in renal failure. Am J Physiol Heart Circ Physiol 2018; 315:H1414-H1424. [PMID: 30028196 DOI: 10.1152/ajpheart.00272.2018] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD. NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.
Collapse
Affiliation(s)
- Melissa Verkaik
- Department of Nephrology and Institute for Cardiovascular Research VU, VU University Medical Center , Amsterdam , The Netherlands
| | - Rio P Juni
- Department of Physiology, Institute for Cardiovascular Research VU, VU University Medical Center , Amsterdam , The Netherlands
| | - Ellen P M van Loon
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen , The Netherlands
| | - Erik M van Poelgeest
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen , The Netherlands
| | - Rick F J Kwekkeboom
- Department of Physiology, Institute for Cardiovascular Research VU, VU University Medical Center , Amsterdam , The Netherlands
| | - Zeineb Gam
- Department of Physiology, Institute for Cardiovascular Research VU, VU University Medical Center , Amsterdam , The Netherlands
| | | | - Pieter M Ter Wee
- Department of Nephrology and Institute for Cardiovascular Research VU, VU University Medical Center , Amsterdam , The Netherlands
| | - Joost G Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen , The Netherlands
| | - Etto C Eringa
- Department of Physiology, Institute for Cardiovascular Research VU, VU University Medical Center , Amsterdam , The Netherlands
| | - Marc G Vervloet
- Department of Nephrology and Institute for Cardiovascular Research VU, VU University Medical Center , Amsterdam , The Netherlands
| | | |
Collapse
|
|
44
|
Nguyen-Tu MS, Nivoit P, Oréa V, Lemoine S, Acquaviva C, Pagnon-Minot A, Fromy B, Sethi JK, Sigaudo-Roussel D. Inflammation-linked adaptations in dermal microvascular reactivity accompany the development of obesity and type 2 diabetes. Int J Obes (Lond) 2018; 43:556-566. [PMID: 30006585 PMCID: PMC6223541 DOI: 10.1038/s41366-018-0148-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 05/26/2018] [Accepted: 06/08/2018] [Indexed: 01/04/2023]
Abstract
Background/Objectives The increased prevalence of obesity has prompted great strides in our understanding of specific adipose depots and their involvement in cardio-metabolic health. However, the impact of obesity on dermal white adipose tissue (dWAT) and dermal microvascular functionality remains unclear. This study aimed to investigate the temporal changes that occur in dWAT and dermal microvascular functionality during the development of diet-induced obesity and type 2 diabetes in mice. Methods Metabolic phenotyping of a murine model of hypercaloric diet (HCD)-induced obesity and type 2 diabetes was performed at three time points that reflected three distinct stages of disease development; 2 weeks of HCD-overweight-metabolically healthy, 4 weeks of HCD-obese-prediabetic and 12 weeks of HCD-obese-type 2 diabetic mice. Expansion of dWAT was characterized histologically, and changes in dermal microvascular reactivity were assessed in response to pressure and the vasodilators SNP and Ach. Results HCD resulted in a progressive expansion of dWAT and increased expression of pro-inflammatory markers (IL1β and COX-2). Impairments in pressure-induced (PIV) and Ach-induced (endothelium-dependent) vasodilation occurred early, in overweight-metabolically healthy mice. Residual vasodilatory responses were NOS-independent but sensitive to COX inhibition. These changes were associated with reductions in NO and adiponectin bioavailability, and rescued by exogenous adiponectin or hyperinsulinemia. Obese-prediabetic mice continued to exhibit impaired Ach-dependent vasodilation but PIV appeared normalized. This normalization coincided with elevated endogenous adiponectin and insulin levels, and was sensitive to NOS, COX and PI3K, inhibition. In obese-type 2 diabetic mice, both Ach-stimulated and pressure-induced vasodilatory responses were increased through enhanced COX-2-dependent prostaglandin response. Conclusions We demonstrate that the development of obesity, metabolic dysfunction and type 2 diabetes, in HCD-fed mice, is accompanied by increased dermal adiposity and associated metaflammation in dWAT. Importantly, these temporal changes are also linked to disease stage-specific dermal microvascular reactivity, which may reflect adaptive mechanisms driven by metaflammation.
Collapse
Affiliation(s)
- Marie-Sophie Nguyen-Tu
- LBTI, UMR CNRS 5305, 69367, Lyon Cedex 07, France.,University of Lyon 1, 69367, Lyon Cedex 07, France
| | - Pierre Nivoit
- LBTI, UMR CNRS 5305, 69367, Lyon Cedex 07, France.,University of Lyon 1, 69367, Lyon Cedex 07, France
| | - Valérie Oréa
- LBTI, UMR CNRS 5305, 69367, Lyon Cedex 07, France.,University of Lyon 1, 69367, Lyon Cedex 07, France
| | | | - Cécile Acquaviva
- LBTI, UMR CNRS 5305, 69367, Lyon Cedex 07, France.,Centre de Biologie et Pathologie Est, University Hospital, Hospices Civils de Lyon, 69677, Bron, France
| | | | - Bérengère Fromy
- LBTI, UMR CNRS 5305, 69367, Lyon Cedex 07, France.,University of Lyon 1, 69367, Lyon Cedex 07, France
| | - Jaswinder K Sethi
- Faculty of Medicine, University of Southampton, Institute of Developmental Sciences Building, Southampton General Hospital, Southampton, SO16 6YD, UK. .,National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, SO16 6YD, UK. .,Institute for Life Sciences, Life Sciences Building 85, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
| | - Dominique Sigaudo-Roussel
- LBTI, UMR CNRS 5305, 69367, Lyon Cedex 07, France. .,University of Lyon 1, 69367, Lyon Cedex 07, France.
| |
Collapse
|
|
45
|
Akoumianakis I, Antoniades C. The interplay between adipose tissue and the cardiovascular system: is fat always bad? Cardiovasc Res 2018; 113:999-1008. [PMID: 28582523 DOI: 10.1093/cvr/cvx111] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 05/31/2017] [Indexed: 12/14/2022] Open
Abstract
Obesity is a risk factor for cardiovascular disease (CVD). However, clinical research has revealed a paradoxically protective role for obesity in patients with chronic diseases including CVD, suggesting that the biological 'quality' of adipose tissue (AT) may be more important than overall AT mass or body weight. Importantly, AT is recognised as a dynamic organ secreting a wide range of biologically active adipokines, microRNAs, gaseous messengers, and other metabolites that affect the cardiovascular system in both endocrine and paracrine ways. Despite being able to mediate normal cardiovascular function under physiological conditions, AT undergoes a phenotypic shift characterised by acquisition of pro-oxidant and pro-inflammatory properties in cases of CVD. Crucially, recent evidence suggests that AT depots such as perivascular AT and epicardial AT are able to modify their phenotype in response to local signals of vascular and myocardial origin, respectively. Utilisation of this unique property of certain AT depots to dynamically track cardiovascular biology may reveal novel diagnostic and prognostic tools against CVD. Better understanding of the mechanisms controlling the 'quality' of AT secretome, as well as the communication links between AT and the cardiovascular system, is required for the efficient management of CVD.
Collapse
Affiliation(s)
- Ioannis Akoumianakis
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Charalambos Antoniades
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| |
Collapse
|
|
46
|
Han F, Li K, Pan R, Xu W, Han X, Hou N, Sun X. Calycosin directly improves perivascular adipose tissue dysfunction by upregulating the adiponectin/AMPK/eNOS pathway in obese mice. Food Funct 2018; 9:2409-2415. [PMID: 29595858 DOI: 10.1039/c8fo00328a] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Perivascular adipose tissue (PVAT) loses its anti-contractile activity in obesity. Calycosin, the major bioactive isoflavonoid, was shown to protect endothelial function. However, effects of calycosin on PVAT function in obesity remain unclear. We aimed to investigate the effects of calycosin on the anti-contractile activity of PVAT in obese mice and its potential mechanisms. Obesity in mice was induced with a high-fat diet, with or without calycosin treatment. Thoracic aorta responses to phenylephrine were determined. AMP protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) levels were analyzed by western blotting. Adiponectin, TNF-α levels and superoxide production were measured in the PVAT. Calycosin treatment significantly increased the anti-contractile response of PVAT, which was impaired in obese mice. This beneficial effect of calycosin was eliminated by treatments of blocking adiponectin, AMPK or eNOS. Similar results were observed for calycosin treatment ex vivo. Treatment of obese mice with calycosin significantly increased adiponectin levels, activated AMPK and eNOS phosphorylation and reduced superoxide production and TNF-α levels in PVAT. Our results indicated that calycosin restored PVAT induced anti-contractile activity and affected PVAT function through the adiponectin/AMPK/eNOS pathway in obese mice.
Collapse
Affiliation(s)
- Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Baylie R, Ahmed M, Bonev AD, Hill-Eubanks DC, Heppner TJ, Nelson MT, Greenstein AS. Lack of direct effect of adiponectin on vascular smooth muscle cell BK Ca channels or Ca 2+ signaling in the regulation of small artery pressure-induced constriction. Physiol Rep 2018; 5:5/16/e13337. [PMID: 28830977 PMCID: PMC5582259 DOI: 10.14814/phy2.13337] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 05/18/2017] [Accepted: 05/20/2017] [Indexed: 12/23/2022] Open
Abstract
The aim of this study was to investigate mechanisms by which adiponectin influences vascular Ca2+ signaling, K+ channel activity and thus contractile tone of small arteries. Vasodilation to adiponectin was studied in mesenteric resistance arteries constricted with intraluminal pressure. Ca2+ signals were characterized using high speed confocal microscopy of intact arteries. Patch clamp investigated the effect of adiponectin on individual VSMC potassium (K+) channel currents. Adiponectin dilated arteries constricted with pressure‐induced tone by approximately 5% and the induced vasodilation was only transient. The dilation to adiponectin was reduced by pharmacological interruption of the Ca2+ spark/large conductance activated K+ (BK) channel pathway but from a physiological perspective, interpretation of the data was limited by the small effect. Neither Adiponectin nor the presence of intact perivascular adipose tissue (PVAT) influenced Ca2+ spark or Ca2+ wave frequency or characteristics. Studied using a perforated patch approach, Adiponectin marginally increased current through the VSMC BK channel but this effect was lost using the whole cell technique with dialysis of the cytoplasm. Adiponectin did not change the frequency or amplitude of Ca2+ spark‐induced transient outward currents (STOC). Overall, our study shows that Adiponectin induces only a small and transient dilation of pressure constricted mesenteric arteries. This vasodilatory effect is likely to be independent of Ca2+ sparks or direct BK channel activation.
Collapse
Affiliation(s)
- Rachael Baylie
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Majid Ahmed
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Adrian D Bonev
- Department of Pharmacology, University of Vermont, Burlington, Vermont
| | | | - Thomas J Heppner
- Department of Pharmacology, University of Vermont, Burlington, Vermont
| | - Mark T Nelson
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.,Department of Pharmacology, University of Vermont, Burlington, Vermont
| | - Adam S Greenstein
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| |
Collapse
|
|
48
|
Turaihi AH, Bakker W, van Hinsbergh VWM, Serné EH, Smulders YM, Niessen HWM, Eringa EC. Insulin Receptor Substrate 2 Controls Insulin-Mediated Vasoreactivity and Perivascular Adipose Tissue Function in Muscle. Front Physiol 2018; 9:245. [PMID: 29628894 PMCID: PMC5876319 DOI: 10.3389/fphys.2018.00245] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 03/06/2018] [Indexed: 11/16/2022] Open
Abstract
Introduction: Insulin signaling in adipose tissue has been shown to regulate insulin's effects in muscle. In muscle, perivascular adipose tissue (PVAT) and vascular insulin signaling regulate muscle perfusion. Insulin receptor substrate (IRS) 2 has been shown to control adipose tissue function and glucose metabolism, and here we tested the hypothesis that IRS2 mediates insulin's actions on the vessel wall as well as the vasoactive properties of PVAT. Methods: We studied PVAT and muscle resistance arteries (RA) from littermate IRS2+/+ and IRS2−/− mice and vasoreactivity by pressure myography, vascular insulin signaling, adipokine expression, and release and PVAT morphology. As insulin induced constriction of IRS2+/+ RA in our mouse model, we also exposed RA's of C57/Bl6 mice to PVAT from IRS2+/+ and IRS2−/− littermates to evaluate vasodilator properties of PVAT. Results: IRS2−/− RA exhibited normal vasomotor function, yet a decreased maximal diameter compared to IRS2+/+ RA. IRS2+/+ vessels unexpectedly constricted endothelin-dependently in response to insulin, and this effect was absent in IRS2−/− RA due to reduced ERK1/2activation. For evaluation of PVAT function, we also used C57/Bl6 vessels with a neutral basal effect of insulin. In these experiments insulin (10.0 nM) increased diameter in the presence of IRS2+/+ PVAT (17 ± 4.8, p = 0.014), yet induced a 10 ± 7.6% decrease in diameter in the presence of IRS2−/− PVAT. Adipocytes in IRS2−/− PVAT (1314 ± 161 μm2) were larger (p = 0.0013) than of IRS2+/+ PVAT (915 ± 63 μm2). Adiponectin, IL-6, PAI-1 secretion were similar between IRS2+/+ and IRS2−/− PVAT, as were expression of pro-inflammatory genes (TNF-α, CCL2) and adipokines (adiponectin, leptin, endothelin-1). Insulin-induced AKT phosphorylation in RA was similar in the presence of IRS2−/− and IRS2+/+ PVAT. Conclusion: In muscle, IRS2 regulates both insulin's vasoconstrictor effects, mediating ERK1/2-ET-1 activation, and its vasodilator effects, by mediating the vasodilator effect of PVAT. The regulatory role of IRS2 in PVAT is independent from adiponectin secretion.
Collapse
Affiliation(s)
- Alexander H Turaihi
- Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, Netherlands
| | - Wineke Bakker
- Department of Internal Medicine, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, Netherlands
| | - Victor W M van Hinsbergh
- Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, Netherlands
| | - Erik H Serné
- Department of Internal Medicine, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, Netherlands
| | - Yvo M Smulders
- Department of Internal Medicine, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, Netherlands
| | - Hans W M Niessen
- Department of Pathology and Cardiac Surgery, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, Netherlands
| | - Etto C Eringa
- Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, Netherlands
| |
Collapse
|
|
49
|
Costa RM, Neves KB, Tostes RC, Lobato NS. Perivascular Adipose Tissue as a Relevant Fat Depot for Cardiovascular Risk in Obesity. Front Physiol 2018; 9:253. [PMID: 29618983 PMCID: PMC5871983 DOI: 10.3389/fphys.2018.00253] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 03/06/2018] [Indexed: 12/18/2022] Open
Abstract
Obesity is associated with increased risk of premature death, morbidity, and mortality from several cardiovascular diseases (CVDs), including stroke, coronary heart disease (CHD), myocardial infarction, and congestive heart failure. However, this is not a straightforward relationship. Although several studies have substantiated that obesity confers an independent and additive risk of all-cause and cardiovascular death, there is significant variability in these associations, with some lean individuals developing diseases and others remaining healthy despite severe obesity, the so-called metabolically healthy obese. Part of this variability has been attributed to the heterogeneity in both the distribution of body fat and the intrinsic properties of adipose tissue depots, including developmental origin, adipogenic and proliferative capacity, glucose and lipid metabolism, hormonal control, thermogenic ability, and vascularization. In obesity, these depot-specific differences translate into specific fat distribution patterns, which are closely associated with differential cardiometabolic risks. The adventitial fat layer, also known as perivascular adipose tissue (PVAT), is of major importance. Similar to the visceral adipose tissue, PVAT has a pathophysiological role in CVDs. PVAT influences vascular homeostasis by releasing numerous vasoactive factors, cytokines, and adipokines, which can readily target the underlying smooth muscle cell layers, regulating the vascular tone, distribution of blood flow, as well as angiogenesis, inflammatory processes, and redox status. In this review, we summarize the current knowledge and discuss the role of PVAT within the scope of adipose tissue as a major contributing factor to obesity-associated cardiovascular risk. Relevant clinical studies documenting the relationship between PVAT dysfunction and CVD with a focus on potential mechanisms by which PVAT contributes to obesity-related CVDs are pointed out.
Collapse
Affiliation(s)
- Rafael M Costa
- Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil
| | - Karla B Neves
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Rita C Tostes
- Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil
| | - Núbia S Lobato
- Institute of Health Sciences, Federal University of Goias, Jatai, Brazil
| |
Collapse
|
|
50
|
Yu Y, Du H, Wei S, Feng L, Li J, Yao F, Zhang M, Hatch GM, Chen L. Adipocyte-Derived Exosomal MiR-27a Induces Insulin Resistance in Skeletal Muscle Through Repression of PPARγ. Am J Cancer Res 2018; 8:2171-2188. [PMID: 29721071 PMCID: PMC5928879 DOI: 10.7150/thno.22565] [Citation(s) in RCA: 219] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Accepted: 01/31/2018] [Indexed: 12/12/2022] Open
Abstract
The mechanism by which adipocyte-derived endocrine factors promote insulin resistance in skeletal muscle are not fully understood. MiR-27a is highly expressed in sera of obese individuals with prediabetes and T2DM, and mainly derived by adipose tissues. Thus, miR-27a secreted into circulation by adipose tissue may regulate insulin resistance in skeletal muscle. Methods: The association between miR-27a and insulin resistance in skeletal muscle was determined in obese children, high-fat diet-induced miR-27a knockdown obese mice, db/db mice and C2C12 cells overexpressing miR-27a. The crosstalk mediated by exosomal miR-27a between adipose tissue and skeletal muscle was determined in C2C12 cells incubated with conditioned medium prepared from palmitate-treated 3T3-L1 adipocytes. Results: We showed that serum miR-27a level correlated positively with obesity and insulin resistance in obese children, and that elevated serum miR-27a levels correlated with insulin resistance in leptin receptor-deficient db/db mice, and with obesity and insulin resistance in high-fat diet-fed C57BL/6J mice. MiR-27a released from adipocytes of high-fat diet-fed C57BL/6J mice was associated with triglyceride accumulation. MiR-27a derived from these adipocytes induced insulin resistance in C2C12 skeletal muscle cells through miR-27a-mediated repression of PPARγ and its downstream genes involved in the development of obesity. Conclusions: These results identify a novel crosstalk signaling pathway between adipose tissue and skeletal muscle in the development of insulin resistance, and indicate that adipose tissue-derived miR-27a may play a key role in the development of obesity-triggered insulin resistance in skeletal muscle.
Collapse
|