Predominant role of nuclear versus membrane estrogen receptor α in arterial protection

Implications for estrogen receptor α modulation in cardiovascular prevention/safety

Emmanuel Guivarc’h, Mélissa Buscato, Anne Laure Guihot, Julie Favre, Emilie Vessières, Linda Grimaud, Jamal Wakim, Nada Joe Melhem, Rana Zahreddine, Marine Adlanmerini, Laurent Loufrani, Claude Knauf, John A. Katzenellenbogen, Benita S Katzenellenbogen, Jean Michel Foidart, Pierre Gourdy, Françoise Lenfant, Jean François Arnal, Daniel Henrion, Coralie Fontaine

Research output: Contribution to journalArticle

Abstract

Background—Although estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane-initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane-initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization. Methods and Results—Using mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane-initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II–induced hypertension as well as to allow flow-mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow-mediated arteriolar remodeling. Conclusions—Altogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

Original languageEnglish (US)
Article numbere008950
JournalJournal of the American Heart Association
Volume7
Issue number13
DOIs
StatePublished - Jul 1 2018

Fingerprint

Nuclear Envelope
Estrogen Receptors
Safety
Estrogens
Estetrol
Steroids
Lipoylation
Hypertension
Membranes
Hormone Replacement Therapy
Angiotensins
Atherosclerotic Plaques
Oral Contraceptives
Transgenic Mice
Endothelium
Cysteine
Blood Vessels
Transcription Factors
Cell Membrane
Medicine

Keywords

  • Arteriolar remodeling
  • Atherosclerosis
  • Estrogen
  • Hypertension
  • Nuclear receptor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Predominant role of nuclear versus membrane estrogen receptor α in arterial protection : Implications for estrogen receptor α modulation in cardiovascular prevention/safety. / Guivarc’h, Emmanuel; Buscato, Mélissa; Guihot, Anne Laure; Favre, Julie; Vessières, Emilie; Grimaud, Linda; Wakim, Jamal; Melhem, Nada Joe; Zahreddine, Rana; Adlanmerini, Marine; Loufrani, Laurent; Knauf, Claude; Katzenellenbogen, John A.; Katzenellenbogen, Benita S; Foidart, Jean Michel; Gourdy, Pierre; Lenfant, Françoise; Arnal, Jean François; Henrion, Daniel; Fontaine, Coralie.

In: Journal of the American Heart Association, Vol. 7, No. 13, e008950, 01.07.2018.

Research output: Contribution to journalArticle

Guivarc’h, E, Buscato, M, Guihot, AL, Favre, J, Vessières, E, Grimaud, L, Wakim, J, Melhem, NJ, Zahreddine, R, Adlanmerini, M, Loufrani, L, Knauf, C, Katzenellenbogen, JA, Katzenellenbogen, BS, Foidart, JM, Gourdy, P, Lenfant, F, Arnal, JF, Henrion, D & Fontaine, C 2018, 'Predominant role of nuclear versus membrane estrogen receptor α in arterial protection: Implications for estrogen receptor α modulation in cardiovascular prevention/safety', Journal of the American Heart Association, vol. 7, no. 13, e008950. https://doi.org/10.1161/JAHA.118.008950
Guivarc’h, Emmanuel ; Buscato, Mélissa ; Guihot, Anne Laure ; Favre, Julie ; Vessières, Emilie ; Grimaud, Linda ; Wakim, Jamal ; Melhem, Nada Joe ; Zahreddine, Rana ; Adlanmerini, Marine ; Loufrani, Laurent ; Knauf, Claude ; Katzenellenbogen, John A. ; Katzenellenbogen, Benita S ; Foidart, Jean Michel ; Gourdy, Pierre ; Lenfant, Françoise ; Arnal, Jean François ; Henrion, Daniel ; Fontaine, Coralie. / Predominant role of nuclear versus membrane estrogen receptor α in arterial protection : Implications for estrogen receptor α modulation in cardiovascular prevention/safety. In: Journal of the American Heart Association. 2018 ; Vol. 7, No. 13.
@article{ae6ec006eeb9436a84e88b30120519c4,
title = "Predominant role of nuclear versus membrane estrogen receptor α in arterial protection: Implications for estrogen receptor α modulation in cardiovascular prevention/safety",
abstract = "Background—Although estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane-initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane-initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization. Methods and Results—Using mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane-initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II–induced hypertension as well as to allow flow-mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow-mediated arteriolar remodeling. Conclusions—Altogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.",
keywords = "Arteriolar remodeling, Atherosclerosis, Estrogen, Hypertension, Nuclear receptor",
author = "Emmanuel Guivarc’h and M{\'e}lissa Buscato and Guihot, {Anne Laure} and Julie Favre and Emilie Vessi{\`e}res and Linda Grimaud and Jamal Wakim and Melhem, {Nada Joe} and Rana Zahreddine and Marine Adlanmerini and Laurent Loufrani and Claude Knauf and Katzenellenbogen, {John A.} and Katzenellenbogen, {Benita S} and Foidart, {Jean Michel} and Pierre Gourdy and Fran{\cc}oise Lenfant and Arnal, {Jean Fran{\cc}ois} and Daniel Henrion and Coralie Fontaine",
year = "2018",
month = "7",
day = "1",
doi = "10.1161/JAHA.118.008950",
language = "English (US)",
volume = "7",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "13",

}

TY - JOUR

T1 - Predominant role of nuclear versus membrane estrogen receptor α in arterial protection

T2 - Implications for estrogen receptor α modulation in cardiovascular prevention/safety

AU - Guivarc’h, Emmanuel

AU - Buscato, Mélissa

AU - Guihot, Anne Laure

AU - Favre, Julie

AU - Vessières, Emilie

AU - Grimaud, Linda

AU - Wakim, Jamal

AU - Melhem, Nada Joe

AU - Zahreddine, Rana

AU - Adlanmerini, Marine

AU - Loufrani, Laurent

AU - Knauf, Claude

AU - Katzenellenbogen, John A.

AU - Katzenellenbogen, Benita S

AU - Foidart, Jean Michel

AU - Gourdy, Pierre

AU - Lenfant, Françoise

AU - Arnal, Jean François

AU - Henrion, Daniel

AU - Fontaine, Coralie

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Background—Although estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane-initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane-initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization. Methods and Results—Using mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane-initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II–induced hypertension as well as to allow flow-mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow-mediated arteriolar remodeling. Conclusions—Altogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

AB - Background—Although estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane-initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane-initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization. Methods and Results—Using mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane-initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II–induced hypertension as well as to allow flow-mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow-mediated arteriolar remodeling. Conclusions—Altogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

KW - Arteriolar remodeling

KW - Atherosclerosis

KW - Estrogen

KW - Hypertension

KW - Nuclear receptor

UR - http://www.scopus.com/inward/record.url?scp=85049669849&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049669849&partnerID=8YFLogxK

U2 - 10.1161/JAHA.118.008950

DO - 10.1161/JAHA.118.008950

M3 - Article

VL - 7

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 13

M1 - e008950

ER -