Estrogen Receptors (cid:1) and (cid:2) Mediate Contribution of Bone Marrow–Derived Endothelial Progenitor Cells to Functional Recovery After Myocardial Infarction

Background —Estradiol (E 2 ) modulates the kinetics of circulating endothelial progenitor cells (EPCs) and favorably affects neovascularization after ischemic injury. However, the roles of estrogen receptors (cid:1) (ER (cid:1) ) and (cid:2) (ER (cid:2) ) in EPC biology are largely unknown. Methods and Results —In response to E 2 , migration, tube formation, adhesion, and estrogen-responsive element– dependent gene transcription activities were severely impaired in EPCs obtained from ER (cid:1) -knockout mice (ER (cid:1) KO) and moderately impaired in ER (cid:2) KO EPCs. The number of ER (cid:1) (cid:1)(cid:2) EPCs (42.4 (cid:3) 1.5; P (cid:4) 0.001) and ER (cid:2) KO EPCs (55.4 (cid:3) 1.8; P (cid:5) 0.03) incorporated into the ischemic border zone was reduced as compared with wild-type (WT) EPCs (72.5 (cid:3) 1.3). In bone marrow transplantation (BMT) models, the number of mobilized endogenous EPCs in E 2 -treated mice was significantly reduced in ER (cid:1) KO BMT (WT mice transplanted with ER (cid:1) KO bone marrow) (2.03 (cid:3) 0.18%; P (cid:5) 0.004 versus WT BMT) and ER (cid:2) KO BMT (2.62 (cid:3) 0.07%; P (cid:5) 0.02 versus WT) compared with WT BMT (2.87 (cid:3) 0.13%) (WT to WT BMT as control) mice. Capillary density at the border zone of ischemic myocardium also was significantly reduced in ER (cid:1) KO BMT and ER (cid:2) KO BMT compared with WT mice (WT BMT, 1718 (cid:3) 75/mm 2 ; ER (cid:1) KO BMT, 1107 (cid:3) 48/mm 2 ; ER (cid:2) KO BMT, 1567 (cid:3) 50/mm 2 ). ER (cid:1) mRNA was expressed more abundantly on EPCs compared with ER (cid:2) . Moreover, vascular endothelial growth factor was significantly downregulated on ER (cid:1) KO EPCs compared with WT EPCs both in vitro and in vivo. and to E 2 EPC activation and tissue incorporation and to preservation of cardiac function after to upregulation of vascular factor, of an effect of E 2 EPC biology. the importance of bone marrow–derived EPC phenotype in ischemic tissue repair. of phenol red and estrogen derived serum. After days in culture, the cells were used as an EPC-rich cell population for cell function studies and real-time polymerase chain reaction (RT-PCR).

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