title: The Activation Function-1 of Estrogen Receptor Alpha Prevents Arterial Neointima Development Through a Direct Effect on Smooth Muscle Cells.
abstract: BACKGROUND
  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.
  
  
  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.
authors: 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.).
authors: Natalia F
authors: NF
authors: Smirnova
authors: 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.).
authors: Coralie
authors: C
authors: Fontaine
authors: 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.).
authors: Mélissa
authors: M
authors: Buscato
authors: 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.).
authors: Adrien
authors: A
authors: Lupieri
authors: 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.).
authors: Alexia
authors: A
authors: Vinel
authors: 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.).
authors: Marie-Cécile
authors: MC
authors: Valera
authors: 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.).
authors: Maeva
authors: M
authors: Guillaume
authors: 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.).
authors: Nicole
authors: N
authors: Malet
authors: 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.).
authors: Jean-Michel
authors: JM
authors: Foidart
authors: 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.).
authors: Isabelle
authors: I
authors: Raymond-Letron
authors: 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.).
authors: Francoise
authors: F
authors: Lenfant
authors: 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.).
authors: Pierre
authors: P
authors: Gourdy
authors: 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.).
authors: Benita S
authors: BS
authors: Katzenellenbogen
authors: 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.).
authors: John A
authors: JA
authors: Katzenellenbogen
authors: 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.).
authors: Muriel
authors: M
authors: Laffargue
authors: 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.).
authors: Jean-Francois
authors: JF
authors: Arnal
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005263:Femoral Artery / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D006965:Hyperplasia; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D058426:Neointima / Q000235:genetics / Q000378:metabolism*; D010052:Ovariectomy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism
chemical_list: D000199:Actins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D004958:Estradiol
keywords: estradiol; estrogen receptor alpha; mice; myocytes; smooth muscle