Membrane estrogen receptor alpha (ERα) participates in flow-mediated dilation in a ligand-independent manner
Julie Favre, Emilie Vessieres, Anne-Laure Guihot, Coralyne Proux, Linda Grimaud, Jordan Rivron, Manuela CL Garcia, Léa Réthoré, Rana Zahreddine, Morgane Davezac, Chanaelle Fébrissy, Marine Adlanmerini, Laurent Loufrani, Vincent Procaccio, Jean-Michel Foidart, Gilles Flouriot, Françoise Lenfant, Coralie Fontaine, Jean-François Arnal, Daniel Henrion
Abstract
Estrogen receptor alpha (ERα) activation by estrogens prevents atheroma through its nuclear action, whereas plasma membrane-located ERα accelerates endothelial healing. The genetic deficiency of ERα was associated with a reduction in flow-mediated dilation (FMD) in one man. Here, we evaluated ex vivo the role of ERα on FMD of resistance arteries. FMD, but not agonist (acetylcholine, insulin)-mediated dilation, was reduced in male and female mice lacking ERα ( Esr1 -/- mice) compared to wild-type mice and was not dependent on the presence of estrogens. In C451A-ERα mice lacking membrane ERα, not in mice lacking AF2-dependent nuclear ERα actions, FMD was reduced, and restored by antioxidant treatments. Compared to wild-type mice, isolated perfused kidneys of C451A-ERα mice revealed a decreased flow-mediated nitrate production and an increased H 2 O 2 production. Thus, endothelial membrane ERα promotes NO bioavailability through inhibition of oxidative stress and thereby participates in FMD in a ligand-independent manner.