Membrane estrogen receptor alpha (ER alpha) participates in flow-mediated dilation in a ligand-independent manner

Estrogen receptor alpha (ER alpha) activation by estrogens prevents atheroma through its nuclear action, whereas plasma membrane-located ER alpha accelerates endothelial healing. The genetic deficiency of ER alpha was associated with a reduction in flow-mediated dilation (FMD) in one man. Here, we evaluated ex vivo the role of ER alpha on FMD of resistance arteries. FMD, but not agonist (acetylcholine, insulin)-mediated dilation, was reduced in male and female mice lacking ER alpha (Esr1-/- mice) compared to wild-type mice and was not dependent on the presence of estrogens. In C451A-ER alpha mice lacking membrane ER alpha, not in mice lacking AF2-dependent nuclear ER alpha actions, FMD was reduced, and restored by antioxidant treatments. Compared to wild-type mice, isolated perfused kidneys of C451A-ER alpha mice revealed a decreased flow-mediated nitrate production and an increased H2O2 production. Thus, endothelial membrane ER alpha promotes NO bioavailability through inhibition of oxidative stress and thereby participates in FMD in a ligand-independent manner.