Estrogen receptor activation protects against TNF-α-induced endothelial dysfunction.

Lack of estrogen is a cause of cardiovascular disease in men and postmenopausal women. We examined the effects of estrogen receptor (ERs) activation/inactivation on endothelial cells subjected to tumor necrosis factor (TNF) α, 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. The TNF-α induces eNOS and MMP-9 expression and PKB activation. The ER activation by apigenin, a nonsteroidal compound with estrogen-like activity mediated through ER binding-dependent pathways, counteracts these effects. These effects are reversed by classic (ER-α and ER-β) and nonclassic (G-protein-coupled receptor) ER inhibitors (ICI182 780 and pertussis toxin, respectively). Our data suggest that ER activation counteracts endothelial dysfunction induced by TNF-α. 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.