The activation function-1 of estrogen receptor alpha prevents arterial neointima development through a direct effect on smooth muscle cells

Natalia F. Smirnova, Coralie Fontaine, Mélissa Buscato, Adrien Lupieri, Alexia Vinel, Marie Cécile Valera, Maeva Guillaume, Nicole Malet, Jean Michel Foidart, Isabelle Raymond-Letron, Francoise Lenfant, Pierre Gourdy, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Muriel Laffargue, Jean Francois Arnal

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)770-777
Number of pages8
JournalCirculation Research
Volume117
Issue number9
DOIs
StatePublished - Oct 9 2015

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Neointima
Estrogen Receptor alpha
Estrogen Receptors
Smooth Muscle Myocytes
Vascular Smooth Muscle
Hyperplasia
Membranes
Cell Proliferation
Selective Estrogen Receptor Modulators
Estrogen Receptor beta
Thigh
Vascular Diseases
Transgenic Mice
Endothelium
Estradiol
Estrogens

Keywords

  • estradiol
  • estrogen receptor alpha
  • mice
  • myocytes
  • smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

The activation function-1 of estrogen receptor alpha prevents arterial neointima development through a direct effect on smooth muscle cells. / 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.

In: Circulation Research, Vol. 117, No. 9, 09.10.2015, p. 770-777.

Research output: Contribution to journalArticle

Smirnova, NF, Fontaine, C, Buscato, M, Lupieri, A, Vinel, A, Valera, MC, Guillaume, M, Malet, N, Foidart, JM, Raymond-Letron, I, Lenfant, F, Gourdy, P, Katzenellenbogen, BS, Katzenellenbogen, JA, Laffargue, M & Arnal, JF 2015, 'The activation function-1 of estrogen receptor alpha prevents arterial neointima development through a direct effect on smooth muscle cells', Circulation Research, vol. 117, no. 9, pp. 770-777. https://doi.org/10.1161/CIRCRESAHA.115.306416
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. / The activation function-1 of estrogen receptor alpha prevents arterial neointima development through a direct effect on smooth muscle cells. In: Circulation Research. 2015 ; Vol. 117, No. 9. pp. 770-777.
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abstract = "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.",
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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

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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