Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 6, Pages 2053-2058Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0808742106
Keywords
atherosclerosis; reendothelialization; vasculoprotection
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Full-length 66-kDa estrogen receptor alpha(ER alpha) 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 alpha 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 alpha AF-1 in the vasculoprotective actions of E2, we generated a targeted deletion of the ER alpha A/B domain in the mouse. In these ER alpha 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 alpha AF-1(+/+) LDLr-/- (low-density lipoprotein receptor) and ER alpha AF-1(0) LDLr-/- mice fed with a hyper-cholesterolemic 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 alpha AF-1 is dispensable for the atheroprotective action of endogenous estrogens. We conclude that ER alpha 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 alpha with minimal activation of ER alpha AF-1 could retain beneficial vascular actions, while minimizing the sexual effects. PHYSIOLOGY
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