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

Full-length 66-kDa estrogen receptorα (ERα) 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 ERα 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 ERαAF-1 in the vasculoprotective actions of E2, we generated a targeted deletion of the ERα A/B domain in the mouse. In these ERαAF-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 ERαAF-1+/+LDLR-/- (low-density lipoprotein receptor) and ERαAF-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 ERαAF-1 is dispensable for the atheroprotective action of endogenous estrogens. We conclude that ERαAF-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 ERα with minimal activation of ERαAF-1 could retain beneficial vascular actions, while minimizing the sexual effects. [Copyright &y& Elsevier]