Published online before print November 6, 2006, doi: 10.1161/CIRCULATIONAHA.106.631465
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(Circulation. 2006;114:2261-2270.)
© 2006 American Heart Association, Inc.
Molecular Cardiology |
Estrogen Receptors 
and ß Mediate Contribution of Bone Marrow–Derived Endothelial Progenitor Cells to Functional Recovery After Myocardial Infarction
From the Division of Cardiovascular Research, St Elizabeth Medical Center of Boston, Tufts University School of Medicine, Boston, Mass (H.H., M.K.K., A.I., M.I., T.T., G.Q., J.A., Y.T., H.S., M.S., A.W., E.B., Y.Z., R.K., D.W.L.), and Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan (M.I.).
Correspondence to Douglas W. Losordo, MD, Cardiovascular Research, Caritas St. Elizabeth Medical Center of Boston, 736 Cambridge St, Boston, MA 02135. E-mail douglas.losordo{at}tufts.edu
Received April 3, 2006; revision received July 6, 2006; accepted August 11, 2006.
Background— Estradiol (E2) modulates the kinetics of circulating endothelial progenitor cells (EPCs) and favorably affects neovascularization after ischemic injury. However, the roles of estrogen receptors 
(ER) and ß (ERß) in EPC biology are largely unknown.
Methods and Results— In response to E2, migration, tube formation, adhesion, and estrogen-responsive element–dependent gene transcription activities were severely impaired in EPCs obtained from ER-knockout mice (ERKO) and moderately impaired in ERßKO EPCs. The number of ERKO EPCs (42.4±1.5; P<0.001) and ERßKO EPCs (55.4±1.8; P=0.03) incorporated into the ischemic border zone was reduced as compared with wild-type (WT) EPCs (72.5±1.3). In bone marrow transplantation (BMT) models, the number of mobilized endogenous EPCs in E2-treated mice was significantly reduced in ERKO BMT (WT mice transplanted with ERKO bone marrow) (2.03±0.18%; P=0.004 versus WT BMT) and ERßKO BMT (2.62±0.07%; P=0.02 versus WT) compared with WT BMT (2.87±0.13%) (WT to WT BMT as control) mice. Capillary density at the border zone of ischemic myocardium also was significantly reduced in ERKO BMT and ERßKO BMT compared with WT mice (WT BMT, 1718±75/mm2; ERKO BMT, 1107±48/mm2; ERßKO BMT, 1567±50/mm2). ER mRNA was expressed more abundantly on EPCs compared with ERß. Moreover, vascular endothelial growth factor was significantly downregulated on ERKO EPCs compared with WT EPCs both in vitro and in vivo.
Conclusions— Both ER and ERß contribute to E2-mediated EPC activation and tissue incorporation and to preservation of cardiac function after myocardial infarction. ER plays a more prominent role in this process. Moreover, ER contributes to upregulation of vascular endothelial growth factor, revealing possible mechanisms of an effect of E2 on EPC biology. Finally, these data provide additional evidence of the importance of bone marrow–derived EPC phenotype in ischemic tissue repair.
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