title: 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.
authors.affiliation: Institut de Médecine Moléculaire de Rangueil, Institut National de la Santé et de la Recherche Médicale, Unité 858, Université Toulouse III Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, 31432 Toulouse, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Billon-Galés
authors.forename: Coralie
authors.initials: C
authors.lastname: Fontaine
authors.forename: Cédric
authors.initials: C
authors.lastname: Filipe
authors.forename: Victorine
authors.initials: V
authors.lastname: Douin-Echinard
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Fouque
authors.forename: Gilles
authors.initials: G
authors.lastname: Flouriot
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
authors.forename: Françoise
authors.initials: F
authors.lastname: Lenfant
authors.forename: Henrik
authors.initials: H
authors.lastname: Laurell
authors.forename: Andrée
authors.initials: A
authors.lastname: Krust
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology; D042783:Endothelial Cells / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000502:physiology*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D010052:Ovariectomy; D020011:Protective Agents; D017434:Protein Structure, Tertiary
chemical_list: D047628:Estrogen Receptor alpha; D020011:Protective Agents; D009569:Nitric Oxide; D004958:Estradiol