Iwakura Atsushi, Shastry Shubha, Luedemann Corinne, Hamada Hiromichi, Kawamoto Atsuhiko, Kishore Raj, Zhu Yan, Qin Gangjian, Silver Marcy, Thorne Tina, Eaton Liz, Masuda Haruchika, Asahara Takayuki, Losordo Douglas W
Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
Circulation. 2006 Mar 28;113(12):1605-14. doi: 10.1161/CIRCULATIONAHA.105.553925. Epub 2006 Mar 13.
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.
Myocardial infarction (MI) was induced by ligation of the left coronary artery in ovariectomized mice receiving either 17beta-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.
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.
近期数据表明，雌二醇可通过内皮型一氧化氮合酶（eNOS）依赖机制调节内皮祖细胞（EPCs）的动力学。我们推测，雌二醇可增强骨髓（BM）来源的EPCs整合至缺血诱导的新生血管形成部位，从而保护免受缺血性损伤。
通过结扎接受17β - 雌二醇或安慰剂的去卵巢小鼠的左冠状动脉诱导心肌梗死（MI）。在雌二醇治疗的动物中，MI后2周和3周，雌二醇诱导循环EPCs显著增加，且雌二醇治疗的动物中毛细血管密度显著更高。MI后1周和4周，在雌二醇治疗的动物的缺血部位观察到的BM来源的EPCs数量比安慰剂治疗的动物更多。在eNOS基因敲除小鼠中，雌二醇对EPCs动员的作用丧失，急性心肌缺血恢复的功能改善也丧失。MI后，在基础和雌二醇刺激条件下，eNOS基因敲除小鼠中基质金属蛋白酶 - 9（MMP - 9）表达降低，在MMP - 9基因敲除小鼠中，雌二醇对EPCs的动员丧失，并且野生型小鼠MI后雌二醇治疗所带来的功能益处显著减弱。
雌二醇通过eNOS介导增强BM中MMP - 9表达，增加BM来源的EPCs的动员和整合至新生血管形成部位，从而维持缺血组织的完整性。此外，这些数据对于我们理解EPCs在MI后恢复中的作用以及心脏事件中的性别差异具有更广泛的意义。
