Abstract 018: Overexpression Of ERα In Adipose Tissue Contributes To The Anti-contractile Effect Of Mesenteric PVAT By NOX4-induced H 2 O 2

Abstract

Perivascular adipose tissue (PVAT) induces a significant anti-contractile effect on vasculature, secreting relaxing and constricting factors. It is well established that the PVAT anti-contractile function is lost in cardiometabolic diseases, including obesity. Estrogen receptor alpha (ERα) is known to play a crucial role in the function of adipose tissues and its activation has been associated with adipogenesis by redox balance. In addition, NADPH oxidase 4 (NOX4) is an enzyme that contribute to adipose tissue differentiation and intracellular H 2 O 2 generation. While ERα are expressed in adipose tissue, but their potential role in PVAT function is unknown. To test the hypothesis, adipose tissue specific ERα overexpressing female mice at 30 weeks old were used. We aimed to determine whether the overexpression of ERα would enhance the anti-contractile effect of PVAT by NOX4-induced H 2 O 2 . The high-fat diet (40% fat) was administered for 20 weeks and mesenteric resistance arteries, with and without PVAT, were isolated and used for measurements of vascular function, protein levels (Western blot) and redox signaling (Amplex Red). The higher-fat diet increases the weigh in ~ 80% in Wild Type (WT) and ERα (p>0.05). The anti-contractile effect of PVAT was exacerbated in arteries of ERα mice than WT [Area under the curve (AUC): WT 369±2 vs. ERα 230±1 p<0.05). NOX1/4 inhibitor (GSK136901) increased the vasoconstriction only in arteries from ERα mice (WT 348 ±4 vs. ERα 580±5 p<0.05). NOX4 (0.19±0.01 vs 2.3±0.6) and H 2 O 2 (> 70%) levels were higher in PVAT from ERα mice than WT. In addition, 6 uM of H 2 O 2 , concentration corresponding to the observed in PVAT from ERα mice, induced vasodilatation in arteries from WT. On the other hand, a high-fat diet abrogates the anti-contractile effect of PVAT (WT with PVAT 233±1 vs. without PVAT 241±4) and has partially restored in the ERα, analyzing LogEC 50 (with PVAT 5±0.7 and without PVAT 6±0.8 M). In addition, H 2 O 2 levels (>50%) were higher in PVAT from the high fat diet fed ERα mice, but NOX4 levels did not change. In summary, overexpression of ERα increases H 2 O 2 levels derived from NOX4, contributing to the anti-contractile effect of PVAT in healthy animals. This effect is partially restored in mice on a high-fat diet with overexpressed ERα.