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

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 heterogeneous tissue that surrounds most peripheral blood vessels. In physiological conditions, PVAT has an anticontractile effect on the vasculature. However, in several diseases, PVAT switches its phenotype to become procontractile. 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>1</i>) increase the anticontractile effect of PVAT in chow diet conditions and <i>2</i>) 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 an HFD for 19 wk. We observed that ERα^OE amplifies the anticontractile 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 an HFD, via the same anticontractile 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 postmenopausal women.<b>NEW & NOTEWORTHY</b> We have revealed for the first time that overexpression of adipose tissue estrogen receptor α (ERα^OE) amplifies the anticontractile effect of mesenteric PVAT via the biosynthesis of NADPH oxidase 4 (NOX4)-derived hydrogen peroxide (H₂O₂), and this overexpression is protective against HFD-induced PVAT dysfunction. Collectively, these data demonstrate an important mechanism by which ERα signaling is vasculoprotective in the context of PVAT.