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.


RESULTS
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.


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.
Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
Atsushi
A
Iwakura
Shubha
S
Shastry
Corinne
C
Luedemann
Hiromichi
H
Hamada
Atsuhiko
A
Kawamoto
Raj
R
Kishore
Yan
Y
Zhu
Gangjian
G
Qin
Marcy
M
Silver
Tina
T
Thorne
Liz
L
Eaton
Haruchika
H
Masuda
Takayuki
T
Asahara
Douglas W
DW
Losordo
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000628:therapy*; D017202:Myocardial Ischemia / Q000473:pathology / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism* / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D010052:Ovariectomy; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
D004958:Estradiol; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse