Smirnova Natalia F, Fontaine Coralie, Buscato Mélissa, Lupieri Adrien, Vinel Alexia, Valera Marie-Cécile, Guillaume Maeva, Malet Nicole, Foidart Jean-Michel, Raymond-Letron Isabelle, Lenfant Francoise, Gourdy Pierre, Katzenellenbogen Benita S, Katzenellenbogen John A, Laffargue Muriel, Arnal Jean-Francois
From the Department of Vascular Biology of the Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse 3, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France (N.F.S., C.F., M.B., A.L., A.V., M.-C.V., M.G., N.M., F.L., P.G., M.L., J.-F.A.); Laboratory of Tumor and Developmental Biology, GIGA-Cancer, Université de Liège, Groupe Interdisciplinaire de Génoprotéomique Appliquée, Liège, Belgique (J.-M.F.); UMR INRA/DGER 1225, Université de Toulouse, INP, ENVT, Toulouse, France (I.R.-L.); Departments of Molecular and Integrative Biology (B.S.K.) and Chemistry, University of Illinois at Urbana-Champaign (J.A.K.).
Circ Res. 2015 Oct 9;117(9):770-8. doi: 10.1161/CIRCRESAHA.115.306416. Epub 2015 Aug 27.
17β-Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor α (ERα) via 2 activation functions, AF1 and AF2, and can also activate membrane ERα. The role of E2 on the endothelium relies on membrane ERα activation, but the molecular mechanisms of its action on vascular smooth muscle cells (VSMCs) are not fully understood.
The aim of this study was to determine which cellular target and which ERα subfunction are involved in the preventive action of E2 on neointimal hyperplasia.
To trigger neointimal hyperplasia of VSMC, we used a mouse model of femoral arterial injury. Cre-Lox models were used to distinguish between the endothelial- and the VSMC-specific actions of E2. The molecular mechanisms underlying the role of E2 were further characterized using both selective ERα agonists and transgenic mice in which the ERαAF1 function had been specifically invalidated. We found that (1) the selective inactivation of ERα in VSMC abrogates the neointimal hyperplasia protection induced by E2, whereas inactivation of endothelial and hematopoietic ERα has no effect; (2) the selective activation of membrane ERα does not prevent neointimal hyperplasia; and (3) ERαAF1 is necessary and sufficient to inhibit postinjury VSMC proliferation.
Altogether, ERαAF1-mediated nuclear action is both necessary and sufficient to inhibit postinjury arterial VSMC proliferation, whereas membrane ERα largely regulates the endothelial functions of E2. This highlights the exquisite cell/tissue-specific actions of the ERα subfunctions and helps to delineate the spectrum of action of selective ER modulators.
17β-雌二醇（E2）在血管疾病中发挥着多种有益作用。它通过核雌激素受体α（ERα）的两个激活功能域AF1和AF2调节基因转录，还能激活膜性ERα。E2对内皮的作用依赖于膜性ERα的激活，但其对血管平滑肌细胞（VSMC）作用的分子机制尚未完全明确。
本研究旨在确定E2对内膜增生的预防作用涉及哪些细胞靶点以及ERα的哪些亚功能。
为诱导VSMC内膜增生，我们采用了股动脉损伤的小鼠模型。利用Cre-Lox模型区分E2在内皮细胞和VSMC中的特异性作用。使用选择性ERα激动剂和ERαAF1功能已被特异性敲除的转基因小鼠，进一步阐明E2作用的分子机制。我们发现：（1）VSMC中ERα的选择性失活消除了E2诱导的内膜增生保护作用，而内皮细胞和造血细胞中ERα的失活则无此影响；（2）膜性ERα的选择性激活不能预防内膜增生；（3）ERαAF1对抑制损伤后VSMC增殖既必要又充分。
总之，ERαAF1介导的核作用对抑制损伤后动脉VSMC增殖既必要又充分，而膜性ERα主要调节E2的内皮功能。这突出了ERα亚功能在细胞/组织中的特异性作用，并有助于描绘选择性雌激素受体调节剂的作用谱。
