Published online before print March 13, 2006, doi: 10.1161/CIRCULATIONAHA.105.553925
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(Circulation. 2006;113:1605-1614.)
© 2006 American Heart Association, Inc.
Molecular Cardiology |
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
From the Division of Cardiovascular Research, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass (A.I., S.S., C.L., H.H., R.K., Y.Z., G.Q., M.S., T.T., L.E., D.W.L.); and the Division of Regenerative Medicine, Institute of Biomedical Research and Innovation, Kobe, Japan (A.K., H.M., T.A.).
Correspondence to Douglas W. Losordo, MD, St. Elizabeth’s Medical Center of Boston, 736 Cambridge St, Boston, MA 02135. E-mail douglas.losordo{at}tufts.edu
Received August 17, 2004; de novo received April 5, 2005; revision received January 16, 2006; accepted January 20, 2006.
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 17ß-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.
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