Overexpression of adipose tissue ERα enhances PVAT anti-contractility via NOX4-derived H2O2 and is protective against high fat diet-induced dysfunction.

Abstract

Menopause has unequivocally been associated with cardiovascular risk and obesity. Loss of estrogen bioavailability is a hallmark of menopause. Estrogen is generally considered vasculoprotective, with estrogen receptor α (ERα) being the predominant receptor subtype that mediates these positive effects. Similarly, estrogen and ERα are known to stimulate white adipose tissue metabolism. However, it is unknown whether ERα could exert a beneficial effect on mesenteric perivascular adipose tissue (PVAT). PVAT is a heterogenous tissue that surrounds most peripheral blood vessels. In physiological conditions, PVAT has an anti-contractile effect on the vasculature. However, in several diseases, PVAT switches its phenotype to become pro contractile. To date, the role of ERα in PVAT function in health and disease is unknown. Therefore, we hypothesized that overexpression of adipose tissue ERα (ERα^OE) would (i) increase the anti-contractile effect of PVAT in chow diet conditions and (ii) protect mice against a high fat diet (HFD)-induced PVAT dysfunction. To test this hypothesis, mesenteric resistance arteries, with and without PVAT, were isolated from female ERα^OE mice, which had either been on a regular chow diet or a HFD for 19 weeks. We observed that ERα^OE amplifies the anti contractile effect of mesenteric PVAT via NADPH oxidase 4 (NOX4)-derived hydrogen peroxide (H₂O₂) in chow conditions, and ERα^OE is protective against a dysfunctional PVAT that is observed after a HFD, via the same anti-contractile mechanism. Collectively, these data demonstrate that ERα is vasculoprotective in the context of PVAT. Harnessing this signaling could be important for reducing cardiovascular risk in post-menopausal women.