Endothelial Estrogen Receptor-α Plays a Crucial Role in the Atheroprotective Action of 17β-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. Methods and Results-We first confirmed the key role of estrogen receptor-alpha (ER alpha) in the atheroprotective effect of estradiol, because this action was completely abolished in mice deficient in both the low-density lipoprotein receptor (LDLr) and ER alpha. Second, using chimeric mice with an ER alpha deficiency in the hematopoietic lineage, we showed the persistence of the protective action of estradiol, which suggests the involvement of extrahematopoietic ER alpha. Third, we showed that loxP-flanked ER alpha mice (ER alpha(flox/flox)) bred with Tie2-Cre(+) mice on an LDLr-/- background had complete inactivation of ER alpha 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(+) ER alpha(flox/flox) LDLr-/- mice transplanted with either Tie2-Cre(+) ER alpha(flox/flox) or ER alpha(-/-) bone marrow, whereas it was present in analogous chimeric Tie2-Cre(-) ER alpha(flox/flox) LDLr-/- receivers expressing endothelial ER alpha. Conclusions-We demonstrate directly and for the first time that endothelial ER alpha represents a key target of the atheroprotective effect of estradiol, whereas hematopoietic ER alpha is dispensable. Selective estrogen receptor modulators that mimic the endothelial action of estradiol should now be considered in atheroprotection. (Circulation. 2009;120:2567-2576.)