TY - JOUR
T1 - The activation function-1 of estrogen receptor alpha prevents arterial neointima development through a direct effect on smooth muscle cells
AU - Smirnova, Natalia F.
AU - Fontaine, Coralie
AU - Buscato, Mélissa
AU - Lupieri, Adrien
AU - Vinel, Alexia
AU - Valera, Marie Cécile
AU - Guillaume, Maeva
AU - Malet, Nicole
AU - Foidart, Jean Michel
AU - Raymond-Letron, Isabelle
AU - Lenfant, Francoise
AU - Gourdy, Pierre
AU - Katzenellenbogen, Benita S.
AU - Katzenellenbogen, John A.
AU - Laffargue, Muriel
AU - Arnal, Jean Francois
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/10/9
Y1 - 2015/10/9
N2 - Rationale: 17β-Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor (ER) via 2 activation functions, AF1 and AF2, and can also activate membrane ER. The role of E2 on the endothelium relies on membrane ER 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 ER 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 ER agonists and transgenic mice in which the ER AF1 function had been specifically invalidated. We found that (1) the selective inactivation of ER in VSMC abrogates the neointimal hyperplasia protection induced by E2, whereas inactivation of endothelial and hematopoietic ER has no effect; (2) the selective activation of membrane ER does not prevent neointimal hyperplasia; and (3) ER AF1 is necessary and sufficient to inhibit postinjury VSMC proliferation. Conclusions: Altogether, ER AF1-mediated nuclear action is both necessary and sufficient to inhibit postinjury arterial VSMC proliferation, whereas membrane ER largely regulates the endothelial functions of E2. This highlights the exquisite cell/tissue-specific actions of the ER subfunctions and helps to delineate the spectrum of action of selective ER modulators.
AB - Rationale: 17β-Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor (ER) via 2 activation functions, AF1 and AF2, and can also activate membrane ER. The role of E2 on the endothelium relies on membrane ER 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 ER 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 ER agonists and transgenic mice in which the ER AF1 function had been specifically invalidated. We found that (1) the selective inactivation of ER in VSMC abrogates the neointimal hyperplasia protection induced by E2, whereas inactivation of endothelial and hematopoietic ER has no effect; (2) the selective activation of membrane ER does not prevent neointimal hyperplasia; and (3) ER AF1 is necessary and sufficient to inhibit postinjury VSMC proliferation. Conclusions: Altogether, ER AF1-mediated nuclear action is both necessary and sufficient to inhibit postinjury arterial VSMC proliferation, whereas membrane ER largely regulates the endothelial functions of E2. This highlights the exquisite cell/tissue-specific actions of the ER subfunctions and helps to delineate the spectrum of action of selective ER modulators.
KW - estradiol
KW - estrogen receptor alpha
KW - mice
KW - myocytes
KW - smooth muscle
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U2 - 10.1161/CIRCRESAHA.115.306416
DO - 10.1161/CIRCRESAHA.115.306416
M3 - Article
C2 - 26316608
AN - SCOPUS:84943643272
SN - 0009-7330
VL - 117
SP - 770
EP - 777
JO - Circulation Research
JF - Circulation Research
IS - 9
ER -