Membrane estrogen receptor alpha (ERα) participates in flow-mediated dilation in a ligand-independent manner
Estrogen receptor alpha (ERα) activation by estrogens prevents atheroma through its nuclear action whereas plasma membrane-located ERα accelerates endothelial healing. The genetic deficiency of ERα was associated with a reduction in flow-mediated dilation (FMD) in one man. Here, we evaluated ex vivo the role of ERα on FMD of resistance arteries. FMD, but not agonist (acetylcholine, insulin)-mediated dilation, was reduced in male and female mice lacking ERα (Esr1-/- mice) compared to wild-type mice and was not dependent on the presence of estrogens. In C451A-ERα mice lacking membrane ERα, not in mice lacking AF2-dependent nuclear ERα actions, FMD was reduced, and restored by antioxidant treatments. Compared to wild-type mice, isolated perfused kidneys of C451A-ERα mice revealed a decreased flow-mediated nitrate production and an increased H2O2 production. Thus, endothelial membrane ERα promotes NO bioavailability through inhibition of oxidative stress and thereby participates in FMD in a ligand-independent manner.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files are provided for each figure and supplement
Article and author information
Fondation pour la Recherche Médicale (FRM - DPC20171138957)
- Daniel Henrion
Fondation pour la Recherche Médicale (Equipe FRM DEQ20160334924)
- Jean-Françoise Arnal
Agence Nationale de la Recherche (ANR-18-CE14-0016-01)
- Daniel Henrion
Fondation Lefoulon Delalande (N/A)
- Julie Favre
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: The investigation was conducted in accordance with the guidelines from Directive 2010/63/EU of the European Parliament for the protection of animals used for scientific purposes (authoriza-tion of the laboratory: # 00577). The protocol was approved by the Institutional Animal Care and Use Committee (IACUC): Committee on the Ethics of Animal Experiments (CEAA) of "Pays de la Loire" (permits #14335, #16740, and #16108).The mice were anesthetized with isoflurane (2.5%) and euthanized using a CO2 chamber and every effort was made to minimize suffering.
- Noriaki Emoto, Kobe Pharmaceutical University, Japan
- Received: March 23, 2021
- Accepted: November 26, 2021
- Accepted Manuscript published: November 29, 2021 (version 1)
- Version of Record published: December 16, 2021 (version 2)
© 2021, Favre et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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