Endothelial Estrogen Receptor α Plays an Essential Role in the Coronary and Myocardial Protective Effects of Estradiol in Ischemia/Reperfusion

Objective-To assess the coronary endothelial protective effects of 17 beta-estradiol (E2) and the role of estrogen receptor (ER) alpha in ischemia/reperfusion (I/R). Methods and Results-E2 exerts protective effects in cardiac I/R. However, the implication in vivo of the endothelium and the cellular targets of the anti-ischemic effects of E2 are unknown. Mice were subjected to I/R (30 minutes of I and 1 hour of R) in vivo, after which acetylcholine-induced relaxation of isolated coronary segments was assessed ex vivo. I/R induced a coronary endothelial dysfunction in untreated ovariectomized mice that was prevented by long-term treatment with E2 in wild-type, but not in ER alpha(-/-), mice. Chimeric mice inactivated for ER in the hematopoietic compartment remained protected by E2. Further inactivation of endothelial ER alpha abolished the protective action of E2 on coronary endothelial function in Tie2-Cre(+) ER alpha(f/f) mice. More importantly, E2 significantly limited infarct size in wild-type mice but not in mice deficient in endothelial ER alpha, even in the presence of hematopoietic ER alpha. Conclusion-Endothelial ER alpha plays a crucial role in the E2-induced prevention of endothelial dysfunction after I/R. To our knowledge, we demonstrate for the first time, by using unique genetically modified mice, that targeting endothelial protection per se can confer cardiomyocyte protection in I/R. (Arterioscler Thromb Vasc Biol. 2010;30:2562-2567.)