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
- Daniel Henrion
- Jean-Françoise Arnal
- Daniel Henrion
- 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
© 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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