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Archives of cardiovascular diseases
Volume 102, n° S1
page 8 (mars 2009)
Doi : 10.1016/S1875-2136(09)72140-0
Themes et posters

A007 The transactivating function-1 of estrogen receptor alpha is dispensable for the vasculoprotective actions of estradiol
 

C. Fontaine 1, B. Billon-Gales 1, C. Filipe 1, V. Douin-Echinard 1, M.-J. Fouque 1, G. Flouriot 2, P. Gourdy 1, F. Lenfant 1, H. Laurell 1, A. Krust 3, P. Chambon 3, J.-F. Arnal 1
1 Institut National de la Santé et de la Recherche, Inserm U858, Université Paul Sabatier, Toulouse, France 
2 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6026, Université de Rennes I, Rennes, France 
3 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche, Illkirch, France 

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Full-length 66-kDa estrogen receptor⍺ (ER⍺) 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 ER⍺ 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 ER⍺AF-1 in the vasculoprotective actions of E2, we generated a targeted deletion of the ER⍺ A/B domain in the mouse. In these ER⍺AF-1zero 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-weekold ER⍺AF-1+/+LDLR-/- (low-density lipoprotein receptor) and ER⍺AF-1zeroLDLR-/- mice fed with a hypercholesterolemic diet. In addition, quantification of lesion size on en face preparations of the ic tree of 8-month-old ovariectomized or intact female mice revealed that ER⍺AF-1 is dispensable for the atheroprotective action of endogenous estrogens. We conclude that ER⍺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 ER⍺ with minimal activation of ER⍺AF-1 could retain beneficial vascular actions, while minimizing the sexual effects.

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