Mutation of Arginine 264 on ERα (Estrogen Receptor Alpha) Selectively Abrogates the Rapid Signaling of Estradiol in the Endothelium Without Altering Fertility.
Fiche publication
Date publication
juillet 2020
Journal
Arteriosclerosis, thrombosis, and vascular biology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre
Tous les auteurs :
Adlanmerini M, Chanaelle F, Zahreddine R, Vessières E, Buscato M, Solinhac R, Favre J, Anquetil T, Guihot AL, Boudou F, Raymond-Letron I, Chambon P, Gourdy P, Ohlsson C, Laurell H, Fontaine C, Metivier R, Le Romancer M, Henrion D, Arnal JF, Lenfant F
Lien Pubmed
Résumé
ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17β-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI3-Kinase as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ERα). In contrast to the C451A-ERα, the females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERα protein abundance was normal, the well-described membrane ERα-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ERα-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved.
Mots clés
arginine, estradiol, estrogen receptor alpha, mice, mutation
Référence
Arterioscler. Thromb. Vasc. Biol.. 2020 Jul 9;:ATVBAHA120314159