Estradiol enhances recovery after myocardial infarction by augmenting incorporation of bone marrow-derived endothelial progenitor cells into sites of ischemia-induced neovascularization via endothelial nitric oxide synthase-mediated activation of matrix metalloproteinase-9

Background - Recent data have indicated that estradiol can modulate the kinetics of endothelial progenitor cells (EPCs) via endothelial nitric oxide synthase ( eNOS) - dependent mechanisms. We hypothesized that estradiol could augment the incorporation of bone marrow ( BM) - derived EPCs into sites of ischemia-induced neovascularization, resulting in protection from ischemic injury. Methods and Results - Myocardial infarction (MI) was induced by ligation of the left coronary artery in ovariectomized mice receiving either 17 beta-estradiol or placebo. Estradiol induced significant increases in circulating EPCs 2 and 3 weeks after MI in estradiol- treated animals, and capillary density was significantly greater in estradiol- treated animals. Greater numbers of BM-derived EPCs were observed at ischemic sites in estradiol- treated animals than in placebo-treated animals 1 and 4 weeks after MI. In eNOS-null mice, the effect of estradiol on mobilization of EPCs was lost, as was the functional improvement in recovery from acute myocardial ischemia. A decrease was found in matrix metalloproteinase-9 (MMP-9) expression in eNOS-null mice under basal and estradiol- stimulated conditions after MI, the mobilization of EPCs by estradiol was lost in MMP-9 - null mice, and the functional benefit conferred by estradiol treatment after MI in wild-type mice was significantly attenuated. Conclusions - Estradiol preserves the integrity of ischemic tissue by augmenting the mobilization and incorporation of BM-derived EPCs into sites of neovascularization by eNOS-mediated augmentation of MMP-9 expression in the BM. Moreover, these data have broader implications with regard to our understanding of the role of EPCs in post-MI recovery and on the sex discrepancy in cardiac events.