Endothelial estrogen receptor-alpha plays a crucial role in the atheroprotective action of 17beta-estradiol in low-density lipoprotein receptor-deficient mice.
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.
Billon-Galés
Audrey
A
INSERM U858, CHU et Université de Toulouse III, Toulouse Cedex 4, France.
Fontaine
Coralie
C
Douin-Echinard
Victorine
V
Delpy
Laurent
L
Berges
Hortense
H
Calippe
Bertrand
B
Lenfant
Françoise
F
Laurell
Henrik
H
Guéry
Jean-Charles
JC
Gourdy
Pierre
P
Arnal
Jean-François
JF
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*
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