Journal
EMBO MOLECULAR MEDICINE
Volume 6, Issue 10, Pages 1328-1346Publisher
WILEY
DOI: 10.15252/emmm.201404112
Keywords
endothelium; estetrol; estrogen receptor; uterus
Categories
Funding
- INSERM, Universite de Toulouse III [U1048]
- Faculte de Medecine Toulouse-Rangueil
- Fondation de France
- Conseil Regional Midi-Pyrenees
- Fondation pour la Recherche Medicale (FRM)
- Groupe de Reflexion sur la Recherche Cardiovasculaire
- CNRS
- region Midi-Pyrenees
- European structural funds
- INSERM [U1083-CNRS-UMR 6214]
- CHU
- Universite d'Angers
- Fondation de l'Avenir
- Conseil Regional Pays de la Loire
- F.R.S.-FNRS (Belgium)
- SPW (Belgium) [DGO6]
- IUAP (Belspo, Belgium)
- National Institutes of Health [PHS5R01 DK015556]
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Estetrol (E-4) is a natural estrogen with a long half-life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor alpha (ER alpha) ligand-binding domain bound to 17 beta-estradiol (E-2) and E-4 are very similar, as well as their capacity to activate the two activation functions AF-1 and AF-2 and to recruit the coactivator SRC3. In vivo administration of high doses of E-4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ER alpha actions. However, E-4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane-initiated steroid signaling (MISS). Furthermore, E-4 antagonized E-2 MISS-dependent effects in endothelium but also in MCF-7 breast cancer cell line. This profile of ER alpha activation by E-4, uncoupling nuclear and membrane activation, characterizes E-4 as a selective ER modulator which could have medical applications that should now be considered further.
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