The Activation Function-1 of Estrogen Receptor Alpha Prevents Arterial Neointima Development Through a Direct Effect on Smooth Muscle Cells

RATIONALE: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 activat...

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Published in:Circulation research 2015-10, Vol.117 (9), p.770-778
Main Authors: 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
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Arteries - drug effects
Arteries - metabolism
Arteries - pathology
Cardiology and cardiovascular system
Cell Membrane - metabolism
Cell Nucleus - metabolism
Cell Proliferation - drug effects
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Endothelium, Vascular - pathology
estradiol
Estradiol - pharmacology
estrogen receptor alpha
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Estrogens - pharmacology
Femoral Artery - drug effects
Femoral Artery - injuries
Femoral Artery - metabolism
Hematology
Human health and pathology
Human health sciences
Hyperplasia
Immunohistochemistry
Life Sciences
mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Molecular Medicine
muscle, smooth, vascular
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
myocytes, smooth muscle
Myocytes, Smooth Muscle - drug effects
Myocytes, Smooth Muscle - metabolism
Médecine de la reproduction (Gynécologie, andrologie, obstétrique)
Neointima - genetics
Neointima - metabolism
Ovariectomy
Platelet Endothelial Cell Adhesion Molecule-1 - metabolism
Reproductive medicine (gynecology, andrology, obstetrics)
Sciences de la santé humaine
Tunica Intima - drug effects
Tunica Intima - metabolism
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Summary:RATIONALE: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. OBJECTIVE: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. METHODS AND RESULTS: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. CONCLUSIONS: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.
ISSN:0009-7330
1524-4571
1524-4571
DOI:10.1161/CIRCRESAHA.115.306416