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The transactivating function 1 of estrogen receptor alpha is dispensable for the vasculoprotective actions of 17beta-estradiol.

Abstract：

:Full-length 66-kDa estrogen receptor alpha (ERalpha) 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 ERalpha 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 ERalpha AF-1 in the vasculoprotective actions of E2, we generated a targeted deletion of the ERalpha A/B domain in the mouse. In these ERalphaAF-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 ERalphaAF-1(+/+) LDLr(-/-) (low-density lipoprotein receptor) and ERalphaAF-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 ERalpha AF-1 is dispensable for the atheroprotective action of endogenous estrogens. We conclude that ERalpha 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 ERalpha with minimal activation of ERalpha AF-1 could retain beneficial vascular actions, while minimizing the sexual effects.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Billon-Galés A,Fontaine C,Filipe C,Douin-Echinard V,Fouque MJ,Flouriot G,Gourdy P,Lenfant F,Laurell H,Krust A,Chambon P,Arnal JF

doi

10.1073/pnas.0808742106

subject

Has Abstract

pub_date

2009-02-10 00:00:00

pages

2053-8

issue

eissn

0027-8424

issn

1091-6490

pii

0808742106

journal_volume

106

pub_type

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The transactivating function 1 of estrogen receptor alpha is dispensable for the vasculoprotective actions of 17beta-estradiol.