title: Endothelial estrogen receptor-alpha plays a crucial role in the atheroprotective action of 17beta-estradiol in low-density lipoprotein receptor-deficient mice.
abstract: BACKGROUND
  The prevention of early atheroma by estrogens has been clearly demonstrated in all animal models and appears to be mediated through a direct action on the arterial wall rather than through an effect on the lipoprotein profile. The goal of the present study was to evaluate which cellular target is crucial in this beneficial action of estradiol.
  
  
  RESULTS
  We first confirmed the key role of estrogen receptor-alpha (ERalpha) in the atheroprotective effect of estradiol, because this action was completely abolished in mice deficient in both the low-density lipoprotein receptor (LDLr) and ERalpha. Second, using chimeric mice with an ERalpha deficiency in the hematopoietic lineage, we showed the persistence of the protective action of estradiol, which suggests the involvement of extrahematopoietic ERalpha. Third, we showed that loxP-flanked ERalpha mice (ERalpha(flox/flox)) bred with Tie2-Cre(+) mice on an LDLr(-/-) background had complete inactivation of ERalpha in most hematopoietic and all endothelial cells. Remarkably, in this mouse model, the atheroprotective effect of estradiol was completely abolished. Fourth, the atheroprotective effect of estradiol remained abolished in Tie2-Cre(+) ERalpha(flox/flox) LDLr(-/-) mice transplanted with either Tie2-Cre(+) ERalpha(flox/flox) or ERalpha(-/-) bone marrow, whereas it was present in analogous chimeric Tie2-Cre(-) ERalpha(flox/flox) LDLr(-/-) receivers expressing endothelial ERalpha.
  
  
  CONCLUSIONS
  We demonstrate directly and for the first time that endothelial ERalpha represents a key target of the atheroprotective effect of estradiol, whereas hematopoietic ERalpha is dispensable. Selective estrogen receptor modulators that mimic the endothelial action of estradiol should now be considered in atheroprotection.
authors.affiliation: INSERM U858, CHU et Université de Toulouse III, Toulouse Cedex 4, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Billon-Galés
authors.forename: Coralie
authors.initials: C
authors.lastname: Fontaine
authors.forename: Victorine
authors.initials: V
authors.lastname: Douin-Echinard
authors.forename: Laurent
authors.initials: L
authors.lastname: Delpy
authors.forename: Hortense
authors.initials: H
authors.lastname: Berges
authors.forename: Bertrand
authors.initials: B
authors.lastname: Calippe
authors.forename: Françoise
authors.initials: F
authors.lastname: Lenfant
authors.forename: Henrik
authors.initials: H
authors.lastname: Laurell
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Guéry
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010052:Ovariectomy; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D011973:Receptors, LDL; D004958:Estradiol; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C045073:Cre recombinase; D019426:Integrases