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-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 ER␣AF-1 ؉/؉ LDLr ؊/؊ (low-density lipoprotein receptor) and ER␣AF-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 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.atherosclerosis ͉ reendothelialization ͉ vasculoprotection E pidemiological studies have suggested that both endogenous and exogenous estrogens protect women against cardiovascular diseases. Although the cardiovascular protective effect of conjugated equine estrogens was not confirmed in postmenopausal women enrolled in the Women Health Initiative (1), it is now widely accepted that the elevated mean age of the women (10-15 years postmenopause) largely contributed to the lack of prevention (2, 3). Thus, although the cardiovascular effects of estrogens are far more complex than initially assumed, it is clear that these hormones play important roles in vascular physiology and pathophysiology, with potential therapeutic implications. Indeed, various vasculoprotective actions of 17␤-estradiol (E2), such as atheroprotection (4, 5), increase of NO production (6), prevention of endothelial activation (7) or apoptosis (8), and the acceleration of endothelial healing (9) have been extensively described.The main action of E2 is mediated by 2 nuclear receptors, estrogen receptor (ER) ␣ and ER␤, encoded by 2 distinct genes, Esr1 and Esr2, respectively. ER␣, but not ER␤, is necessary and sufficient to mediate most of the vascular effects of E2, such as the increase in basal NO production (6) and the acceleration of reendothelialization (10). ER␣ can be divided into 6 domains from A to F that harbors 2 transactivation functions (AF-1 and AF-2) located within regions ...

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