0175 : Phenotypic remodeling of perivascular adipose tissue in a rat model of metabolic syndrome: vascular consequences and beneficial impact of exercise training

In order to investigate the contribution of perivascular adipose tissue (PVAT) to arterial function, a total of 55 small arteries harvested from 35 skin biopsies of patients with Metabolic Syndrome and matched controls were mounted as ring preparations in a wire myograph. Contractility to cumulative doses of Norepinephrine in the presence or absence of PVAT showed an anticontractile effect in arteries from healthy volunteers (p=0.009), which was lost in patients with Metabolic Syndrome. Bioassay studies confirmed that PVAT releases a hydrophilic anticontractile factor in health, which is absent in obesity. Using a soluble fragment of the human Type 1 receptor, we identified that the anticontractile factor was adiponectin, which is the sole mediator of vasodilation, acting by increasing endothelial bioavailability of nitric oxide. Significant endothelial dysfunction was observed in patients with Metabolic Syndrome (p<0.001). Quantitative image analysis of adipose tissue revealed significantly increased adipocyte cell size in patients with Metabolic Syndrome, compared with healthy controls (p<0.006). There was immunohistochemical evidence of inflammation with upregulation of TNF-alpha receptor 1 in these patients (p<0.001). Application of exogenous TNF-alpha abolished the anticontractile effect of PVAT by reducing adiponectin bioavailability. Oxidative stress also induced by cytokines TNF-alpha and IL-6 but not IL-1, reduced adiponectin production from PVAT and increased basal tone. When the obese microenvironment was replicated in vitro by inflicting hypoxia on PVAT, adiponectin activity was lost but then rescued by incubation with cytokine antagonists. Further application of the adiponectin receptor fragment abolished PVAT relaxation. We conclude that in healthy arteries, PVAT releases adiponectin which reduces vascular tone. In obesity, this is lost by a cascade of adipocyte hypertrophy, hypoxia, inflammation and oxidative stress. The resulting vasoconstriction contributes to hypertension, hypertriglyceridaemia and insulin resistance. Direct targeting of adiponectin release from PVAT therefore provides a novel therapeutic opportunity in the Metabolic Syndrome.

Download Full-text

Attenuation of cold stress-induced exacerbation of cardiac and adipose tissue pathology and metabolic disorders in a rat model of metabolic syndrome by the glucocorticoid receptor antagonist RU486

Nutrition and Diabetes ◽

10.1038/nutd.2016.14 ◽

2016 ◽

Vol 6 (4) ◽

pp. e207-e207 ◽

Cited By ~ 9

Author(s):

K Nagasawa ◽

N Matsuura ◽

Y Takeshita ◽

S Ito ◽

Y Sano ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Glucocorticoid Receptor ◽

Cold Stress ◽

Receptor Antagonist ◽

Rat Model ◽

Metabolic Disorders ◽

Antagonist Ru486

Download Full-text

Perivascular Adipose Tissue-Enhanced Vasodilation in Metabolic Syndrome Rats by Apelin and N-Acetyl–l-Cysteine-Sensitive Factor(s)

International Journal of Molecular Sciences ◽

10.3390/ijms20010106 ◽

2018 ◽

Vol 20 (1) ◽

pp. 106 ◽

Cited By ~ 2

Author(s):

Satomi Kagota ◽

Kana Maruyama-Fumoto ◽

Saki Iwata ◽

Miho Shimari ◽

Shiori Koyanagi ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Mrna Level ◽

Receptor Activation ◽

At1 Receptor ◽

Mesenteric Arteries ◽

Mrna Levels ◽

Perivascular Adipose Tissue ◽

Age Related ◽

Sensitive Factor

Perivascular adipose tissue (PVAT) can regulate vascular tone. In mesenteric arteries of SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome, vascular dysfunction is compensated by PVAT-dependent mechanisms that disappear with increasing age. In this study, we investigated the mechanisms of the age-related changes and responsible factor(s) involved in the enhancing effects of mesenteric arterial PVAT in SHRSP.ZF. Acetylcholine- and sodium nitroprusside-induced relaxations of isolated arteries were greater with PVAT than without PVAT at 17 and 20 weeks of age (wks), and as expected, this enhancement by the presence of PVAT disappeared at 23 wks. PVAT mRNA levels of angiotensin II type 1 (AT1) receptor-associated protein was less and AT1 receptor was unchanged at 23 wks when compared to 20 wks. At 20 wks, the enhanced acetylcholine-induced relaxation by the presence of PVAT was inhibited by N-acetyl-l-cysteine (NAC). Acetylcholine-induced relaxation of arteries without PVAT was increased in the presence of exogenously added apelin. PVAT mRNA level of apelin was higher in SHRSP.ZF than in control Wistar-Kyoto rats, and the level was decreased with aging. These results suggest that AT1 receptor activation in PVAT, and changes in the regulation of apelin and a NAC-sensitive factor are related to the age-dependent deterioration of the vasodilation enhancing effects of mesenteric arterial PVAT in SHRSP.ZF.

Download Full-text

Dietary Salt Restriction Improves Cardiac and Adipose Tissue Pathology Independently of Obesity in a Rat Model of Metabolic Syndrome

Journal of the American Heart Association ◽

10.1161/jaha.114.001312 ◽

2014 ◽

Vol 3 (6) ◽

Cited By ~ 22

Author(s):

Takuya Hattori ◽

Tamayo Murase ◽

Miwa Takatsu ◽

Kai Nagasawa ◽

Natsumi Matsuura ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Rat Model ◽

Dietary Salt ◽

Salt Restriction ◽

Dietary Salt Restriction

Download Full-text

Time-Dependent Differences in the Influence of Perivascular Adipose Tissue on Vasomotor Functions in Metabolic Syndrome

Metabolic Syndrome and Related Disorders ◽

10.1089/met.2016.0146 ◽

2017 ◽

Vol 15 (5) ◽

pp. 233-239 ◽

Cited By ~ 5

Author(s):

Satomi Kagota ◽

Saki Iwata ◽

Kana Maruyama ◽

John J. McGuire ◽

Kazumasa Shinozuka

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Time Dependent ◽

Perivascular Adipose Tissue

Download Full-text

Aortic dysfunction in metabolic syndrome mediated by perivascular adipose tissue TNFα- and NOX2-dependent pathway

Experimental Physiology ◽

10.1113/ep086818 ◽

2018 ◽

Vol 103 (4) ◽

pp. 590-603 ◽

Cited By ~ 12

Author(s):

Evan DeVallance ◽

Kayla W. Branyan ◽

Kent Lemaster ◽

I. Mark Olfert ◽

David M. Smith ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Perivascular Adipose Tissue ◽

Dependent Pathway

Download Full-text

Influence of exercise and perivascular adipose tissue on coronary artery vasomotor function in a familial hypercholesterolemic porcine atherosclerosis model

Journal of Applied Physiology ◽

10.1152/japplphysiol.00999.2009 ◽

2010 ◽

Vol 108 (3) ◽

pp. 490-497 ◽

Cited By ~ 24

Author(s):

Aaron K. Bunker ◽

M. Harold Laughlin

Keyword(s):

Adipose Tissue ◽

Coronary Artery ◽

Exercise Training ◽

Ang Ii ◽

Perivascular Adipose Tissue ◽

Vasomotor Function ◽

High Fat Diets ◽

Arterial Contraction ◽

Fat Diets

Our lab has shown that left circumflex coronary artery (LCX) perivascular adipose tissue (PAT) blunts endothelin-1 (ET-1)-induced maximal contractions in normal pigs on low- and high-fat diets. Other studies report that PAT exerts anticontractile effects on agonist-induced arterial contraction via release of a relaxing factor that acts on the underlying vasculature. The purpose of this study was to test the hypotheses that PAT blunts LCX contraction in familial hypercholesterolemic pigs and that exercise training (Ex) augments this anticontractile effect. Male familial hypercholesterolemic pigs were divided into Ex ( n = 13) and sedentary (Sed) ( n = 15) groups. LCX reactivity to angiotensin II (ANG II), bradykinin (BK), ET-1, and sodium nitroprusside (SNP) was evaluated in vitro with intact or removed PAT in Sed and Ex familial hypercholesterolemic pigs. LCX relaxation induced by BK and SNP was not altered by Ex or PAT removal. LCX contractions stimulated by ANG II and ET-1 were not significantly altered by Ex or PAT removal across doses; however, Ex did act to significantly reduce ET-1 maximal contractions in familial hypercholesterolemic pig LCX compared with Sed familial hypercholesterolemic pig LCX, independent of PAT ( P < 0.05). We conclude that LCX PAT in Sed and Ex familial hypercholesterolemic pigs exerts no substantial anticontractile influence over LCX vasomotor responses to endogenous constrictors such as ANG II and ET-1. Our results suggest that exercise training significantly reduces familial hypercholesterolemic pig LCX maximal contractile responses to the endogenous constrictor ET-1, independent of PAT.

Download Full-text

Abstract 278: The Glucocorticoid Receptor Antagonist RU486 Ameliorates Cold Stress-induced Exacerbation of Cardiac and Adipose Tissue Pathology and Metabolic Disorders in a Rat Model of Metabolic Syndrome

Hypertension ◽

10.1161/hyp.64.suppl_1.278 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Kai Nagasawa ◽

Natsumi Matsuura ◽

Yuji Minagawa ◽

Shogo Ito ◽

Yusuke Sano ◽

...

Keyword(s):

Gene Expression ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Lipid Metabolism ◽

Cold Stress ◽

Rat Model ◽

Metabolic Disorders ◽

Glucose And Lipid Metabolism ◽

Obese Rats ◽

Antagonist Ru486

Introduction: Chronic stress, when combined with hyperphagia, can affect adiposity and metabolism. However, few studies have reported the effects of cold stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS). We investigated the effects of chronic cold stress and glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology and gene expression and on glucose and lipid metabolism in a rat model of MetS. Methods and Results: We used DahlS.Z-Leprfa/Leprfa (DS/obese) rats which are derived from a cross between Dahl salt-sensitive and Zucker rats and represent a new animal model of MetS. DS/obese rats were exposed to cold stress (ice-cold water, 1 cm depth, 2 h/day) for 4 weeks beginning at 9 weeks of age with or without the GR antagonist RU486 (2 mg/kg/day, sc). Age-matched homozygous lean (DahlS.Z-Lepr+/Lepr+, or DS/lean) littermates of DS/obese rats served as controls. Chronic cold stress exacerbated hypertension as well as left ventricular (LV) hypertrophy, fibrosis and diastolic dysfunction, in a manner sensitive to RU486. Cold stress and RU486 did not affect body weight or visceral and subcutaneous fat mass. In contrast, cold stress further increased superoxide production and NADPH oxidase activity in the heart as well as macrophage infiltration and the expression of proinflammatory genes in LV and visceral fat tissue. RU486 treatment inhibited these changes in gene expression, as well as cardiac oxidative stress and inflammation and adipose tissue inflammation. Cold stress further up-regulated cardiac renin-angiotensin-aldosterone system gene expression as well as the expression of GR and 11β-hydroxysteroid dehydrogenase type 1 genes in LV and visceral adipose tissue, and all of these effects were attenuated by RU486. In addition, RU486 ameliorated the stress-induced deterioration of dyslipidemia (elevations in low-density lipoprotein cholesterol, triglycerides, and free fatty acid) as well as that of glucose intolerance and insulin resistance. Conclusions: The present results indicate that GRs may be involved in cold stress-induced exacerbation of cardiac and adipose tissue pathology as well as that of glucose and lipid metabolism in a rat model of MetS.

Download Full-text

Abstract P171: Comparison Of Modulation Of Renal Arterial Tone By Perivascular Adipose Tissue Between Two Animal Models Of Metabolic Syndrome

Hypertension ◽

10.1161/hyp.78.suppl_1.p171 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Satomi Kagota ◽

Kana Maruyama-Fumoto ◽

Kana Morikawa ◽

Kazumasa Shinozuka

Keyword(s):

Metabolic Syndrome ◽

Animal Model ◽

Sex Differences ◽

Adipose Tissue ◽

Female Rats ◽

Male Rats ◽

Organ Bath ◽

Perivascular Adipose Tissue ◽

Enhancing Effect ◽

Arterial Tone

Sex differences have recently been noticed in the regulation of arterial tone by perivascular adipose tissue (PVAT). In SHRSP.Z- Lepr fa /IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS), we demonstrated that mesenteric and renal PVAT in female rats consistently have an enhancing effect on vasodilation at 23 weeks, an age by which the effect of PVAT is impaired in the male rats. This could explain the sex differences in the prevalence of cardiovascular complications in patients with MetS. Therefore, we determined whether the sex difference in PVAT response also occurs in another animal model of MetS, SHR/NDmcr-cp (SHR-cp) rats.Renal arteries were isolated from male and female 23-week-old SHR-cp rats, and ring preparations with and without PVAT were made. After a stable contraction was obtained by phenylephrine administration, vasodilation in response to acetylcholine was examined using organ bath methods.Vasodilation in arteries without PVAT from female rats was smaller than that in arteries without PVAT from male rats, and presence of PVAT in arteries from female rats increased vasodilation to the same level as that observed in arteries without PVAT from male rats. Furthermore, renal PVAT in male rats was shown to have an enhancing effect on vasodilation.The present study did not identify sex differences in renal PVAT-mediated modulation in SHR-cp rats because the enhancing effects of PVAT did not disappear in male SHR-cp rats, in contrast to that observed in male SHRSP.ZF rats at the same age. The difference in PVAT response in male rats between two MetS models may be due to differences in the severity of MetS symptoms, especially blood pressure, between the models.

Download Full-text