Predominant Role of Nuclear Versus Membrane Estrogen Receptor alpha in Arterial Protection: Implications for Estrogen Receptor alpha Modulation in Cardiovascular Prevention/Safety

Background-Although estrogen receptor alpha (ER alpha) acts primarily as a transcription factor, it can also elicit membrane-initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERa membrane-initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization. Methods and Results-Using mice with ER alpha mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ER alpha plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2 degrees), we sought to fully characterize the respective roles of nuclear versus membrane-initiated steroid signaling in the arterial protection conferred by ER alpha. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II-induced hypertension as well as to allow flow-mediated arteriolar remodeling. By contrast, ER alpha AF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ER alpha with estetrol was able to prevent hypertension and to restore flow-mediated arteriolar remodeling. Conclusions-Altogether, these results reveal an unexpected prominent role of nuclear ER alpha in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ER alpha agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.