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

Atsushi Iwakura, Shubha Shastry, Corinne Luedemann, Hiromichi Hamada, Atsuhiko Kawamoto, Raj Kishore, Yan Zhu, Gangjian Qin, Marcy Silver, Tina Thorne, Liz Eaton, Haruchika Masuda, Takayuki Asahara, Douglas W. Losordo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

170 Scopus citations

Abstract

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 17β-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.

Original languageEnglish (US)
Pages (from-to)1605-1614
Number of pages10
JournalCirculation
Volume113
Issue number12
DOIs
StatePublished - Mar 2006

Keywords

  • Angiogenesis
  • Endothelium
  • Myocardial infarction
  • Nitric oxide synthase
  • Stem cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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