Abstract 11222: Differential Perivascular Adipose Response to Metabolic Challenge Leads to Sexually Dimorphic Cardiovascular Impairment in Early Prediabetes: Possible Role of Estrogen

Abstract

Cardiovascular (CV) risk associated with metabolic dysfunction commences in early stages preceding the emergence of diagnostic markers. In this regard, a protective role of female sex hormones has been observed where males and postmenopausal females are at a higher risk of these complications. Our previous work on non-obese insulin resistant male rats revealed a crucial role for perivascular adipose tissue (PVAT) inflammation in developing CV dysfunction in early prediabetes. This resulted from PVAT hypoxia evoked by increased uncoupling protein 1 (UCP1) expression and adipocyte hypertrophy in response to a dietary metabolic challenge of mild hypercaloric (MHC) feeding . Here, we examined whether estrogen modulated MHC-induced PVAT dysfunction and its CV consequences. Male and female Sprague-Dawley rats (4-5weeks) were randomly allocated into 2 dietary groups: control or MHC diet for 24 weeks. To control for estrogen effect, bilateral ovariectomy was performed on female rat sub-groups after 12 weeks of feeding with or without daily treatment with an oral dose of 17 β -estradiol (E2) of 2.8 μg/ 100 gm of body weight for an additional 12 weeks. Daily food intake, body weight, body composition, blood glucose and insulin levels, echocardiographic parameters, and blood pressure were measured. At week 24; rats were catheterized for invasive hemodynamic examination. Cardiac autonomic neuropathy was assessed by measuring baroreceptor sensitivity using the vasoactive method. After sacrifice, aortic contractility and endothelial function were examined and molecular investigation were performed. Indeed, the absence of endogenous E2 seemed to precipitate an obese phenotype in MHC-fed female rats and instigate CV impairment together with hallmarks of early PVAT dysfunction reminiscent of those observed in male rats. Intriguingly, E2 replacement restored the protective phenotype observed in intact females. E2 treatment mitigated PVAT inflammation without affecting UCP1 expression levels possibly suggesting a direct anti-inflammatory role. Our results present a novel framework for the protective role of E2 interrupting the inflammatory machinery in PVAT, as well as the subsequent CV dysfunction in presence of a dietary metabolic challenge.