Estrogen receptor activation protects against TNFa-induced endothelial dysfunction

Lack of estrogen is a cause of cardiovascular disease in men and postmenopausal women. We examined the effects of estrogen receptors (ERs) activation/inactivation on endothelial cells subjected to tumor necrosis factor (TNF)\u3b1, which is involved in vascular disease pathogenesis. Endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases (MMP)-9 expression, as well as protein kinase B (PKB) activation were evaluated as markers of endothelial dysfunction. TNF\u3b1 induces eNOS and MMP-9 expression and PKB activation. ER activation by apigenin, a non-steroidal compound with estrogen-like activity mediated through ER binding-dependent pathways, counteracts these effects. These effects are reversed by classic (ER\u3b1 and ER\u3b2) and non-classic (GPR30) ER inhibitors (ICI182, 780 and PTX, respectively). Our data suggest that ER activation counteracts endothelial dysfunction induced by TNF\u3b1. The use of ER activators, such as apigenin, may represent a strategy to prevent vascular disease associated with endothelial dysfunction, while avoiding the feminizing effects of estrogens