Predominant role of nuclear versus membrane estrogen receptor α in arterial protection: Implications for estrogen receptor α modulation in cardiovascular prevention/safety

Emmanuel Guivarc’h, Mélissa Buscato, Anne Laure Guihot, Julie Favre, Emilie Vessières, Linda Grimaud, Jamal Wakim, Nada Joe Melhem, Rana Zahreddine, Marine Adlanmerini, Laurent Loufrani, Claude Knauf, John A. Katzenellenbogen, Benita S. Katzenellenbogen, Jean Michel Foidart, Pierre Gourdy, Françoise Lenfant, Jean François Arnal, Daniel Henrion, Coralie Fontaine

Research output: Contribution to journalArticle

Abstract

Background—Although estrogen receptor α (ERα) 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 ERα 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 ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane-initiated steroid signaling in the arterial protection conferred by ERα. 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, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα 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 ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

Original languageEnglish (US)
Article numbere008950
JournalJournal of the American Heart Association
Volume7
Issue number13
DOIs
StatePublished - Jul 1 2018

Keywords

  • Arteriolar remodeling
  • Atherosclerosis
  • Estrogen
  • Hypertension
  • Nuclear receptor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Guivarc’h, E., Buscato, M., Guihot, A. L., Favre, J., Vessières, E., Grimaud, L., Wakim, J., Melhem, N. J., Zahreddine, R., Adlanmerini, M., Loufrani, L., Knauf, C., Katzenellenbogen, J. A., Katzenellenbogen, B. S., Foidart, J. M., Gourdy, P., Lenfant, F., Arnal, J. F., Henrion, D., & Fontaine, C. (2018). Predominant role of nuclear versus membrane estrogen receptor α in arterial protection: Implications for estrogen receptor α modulation in cardiovascular prevention/safety. Journal of the American Heart Association, 7(13), [e008950]. https://doi.org/10.1161/JAHA.118.008950