Perivascular adipose tissue: a driver of sex-specific differences in the vascular outcomes of obesity

Abstract

Obesity is a potent predictor of cardiovascular disease (CVD) and associated risk factors, including hypertension. Perivascular adipose tissue (PVAT) surrounds most blood vessels and modulates vascular tone. Under physiological conditions, PVAT exerts anti-contractile effects and sex differences are apparent in PVAT function. Under obese conditions, PVAT becomes dysregulated which may contribute to vascular dysfunction; how sex impacts the remodelling of PVAT and altered vascular contractility during obesity is unclear. We hypothesise that sex specific PVAT dysfunction in the setting of obesity is an important driver of sex differences in vascular pathologies and CVD risk.Adult (8wk) male and female C57Bl/6J mice received either chow diet (CD; 2.5%kcal fat) or high fat diet (HFD; 58%kcal fat) for 16 weeks (n=8/sex and diet). At 15 weeks of diet, blood pressure was assessed via tail-cuff plethysmography. At 16 weeks of diet, mesenteric arteries were isolated, and PVAT left intact or removed. Wire myography was used to assess the dilatory response to endothelium-dependent acetylcholine (ACh) and endothelium independent sodium nitroprusside (SNP). LogEC50 and %Preconstriction were calculated for each concentration response curve. PVAT was dissected from mesenteric arteries (mPVAT) and flash frozen for bulk RNA sequencing or fixed for histology. Data are mean ± SD and were analysed by two-way ANOVA.Under CD, the removal of PVAT did not change vasodilatory response to ACh or SNP in either sex. Under HFD, male mice showed reduced sensitivity (logEC50 PVAT vs no PVAT, p=0.0349) and maximal dilatory response (%Preconstriction PVAT vs no PVAT, p=0.0119) to ACh. This effect was not observed in females. Moreover, PVAT exerted no effect on dilatory responses to SNP in HFD groups of either sex, indicating an endothelium-dependent effect. Blood pressure was not altered in either sex by HFD. Transcriptomic analysis using RNA sequencing revealed female mPVAT is clearly distinguished from male mPVAT under HFD, but not CD conditions, with significantly down-regulated extracellular matrix remodelling and pro-inflammatory pathways, and significantly upregulated oxidative phosphorylation pathways. Histological analysis revealed potentiated adipocyte hypertrophy and collagen staining in mPVAT from males compared to females under HFD (p=0.034 and p=0.018 respectively).Our study shows that female mice are more protected from adverse effects of HFD, including PVAT-mediated endothelial dysfunction. Our RNA sequencing data provides insights into how pathophysiologic remodelling of mPVAT may contribute to the vascular outcomes of obesity-associated hypertension and suggests that this may be modulated by sex hormones. Further studies will unpick the underlying mechanism to identify potential targets for therapeutic intervention in obesity-associated hypertension. Funded by British Heart Foundation grant FS/19/55/34890. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.