The transactivating function 1 of estrogen receptor alpha is dispensable for the vasculoprotective actions of 17beta-estradiol. - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2009

The transactivating function 1 of estrogen receptor alpha is dispensable for the vasculoprotective actions of 17beta-estradiol.

Résumé

Full-length 66-kDa estrogen receptor alpha (ERalpha) stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal domain and AF-2 in the ligand binding domain. Another physiologically expressed 46-kDa ERalpha isoform lacks the N-terminal A/B domains and is consequently devoid of AF-1. Previous studies in cultured endothelial cells showed that the N-terminal A/B domain might not be required for estradiol (E2)-elicited NO production. To evaluate the involvement of ERalpha AF-1 in the vasculoprotective actions of E2, we generated a targeted deletion of the ERalpha A/B domain in the mouse. In these ERalphaAF-1(0) mice, both basal endothelial NO production and reendothelialization process were increased by E2 administration to a similar extent than in control mice. Furthermore, exogenous E2 similarly decreased fatty streak deposits at the aortic root from both ovariectomized 18-week-old ERalphaAF-1(+/+) LDLr(-/-) (low-density lipoprotein receptor) and ERalphaAF-1(0) LDLr (-/-) mice fed with a hypercholesterolemic diet. In addition, quantification of lesion size on en face preparations of the aortic tree of 8-month-old ovariectomized or intact female mice revealed that ERalpha AF-1 is dispensable for the atheroprotective action of endogenous estrogens. We conclude that ERalpha AF-1 is not required for three major vasculoprotective actions of E2, whereas it is necessary for the effects of E2 on its reproductive targets. Thus, selective ER modulators stimulating ERalpha with minimal activation of ERalpha AF-1 could retain beneficial vascular actions, while minimizing the sexual effects.

Dates et versions

hal-00369691 , version 1 (20-03-2009)

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Citer

Audrey Billon-Galés, Coralie Fontaine, Cédric Filipe, Victorine Douin-Echinard, Marie-José Fouque, et al.. The transactivating function 1 of estrogen receptor alpha is dispensable for the vasculoprotective actions of 17beta-estradiol.. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106 (6), pp.2053-8. ⟨10.1073/pnas.0808742106⟩. ⟨hal-00369691⟩
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