Full length 66kDa estrogen receptor alpha (ER) stimulates target gene transcription through two activation functions (AF), AF-1 in the N-terminal domain and AF-2 in the ligand binding domain. Another physiologically expressed 46kDa ER isoform lacks the N-terminal A/B domains and is consequently devoid of AF-1. To evaluate the involvement of ER AF-1 and AF-2 in the vasculoprotective actions of estradiol (E2), we generated a targeted deletion of the ER A/B domain in the mouse named ERAF-10 mice, and a targeted deletion of amino acids 543–549 and thus deficient in AF-2 (named ERAF-20 mice).

Both basal endothelial NO production was increased by E2 administration in a similar extent than in control mice. E2 similarly decreased fatty streak deposits at the aortic root from both ovariectomized 18 week-old ERAF-1+/+ LDL-r-/- (Low Density Lipoprotein receptor) and ERAF-10 LDL-r-/- mice fed with a hypercholesterolemic diet. We conclude that ER AF-1 is not required for the vasculoprotective actions of E2, whereas it is necessary for the effects of E2 on its reproductive targets. Thus, Selective Estrogen Receptor Modulators stimulating ER independently of the A/B domain and thereby with minimal activation of ER AF-1 could retain beneficial vascular actions, while minimizing the sexual effects.

The results concerning ERAF-20 mice are in process and will be available at the end of 2010, and the precise role of AF2 in these actions will be presented.