Estrogen Receptors α and β Mediate Contribution of Bone Marrow–Derived Endothelial Progenitor Cells to Functional Recovery After Myocardial Infarction

Abstract

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 α (ERα) and β (ERβ) 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 ERα-knockout mice (ERαKO) and moderately impaired in ERβKO EPCs. The number of ERαΚΟ EPCs (42.4±1.5; P <0.001) and ERβKO 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 E 2 -treated mice was significantly reduced in ERαKO BMT (WT mice transplanted with ERαKO bone marrow) (2.03±0.18%; P =0.004 versus WT BMT) and ERβKO 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 ERαKO BMT and ERβKO BMT compared with WT mice (WT BMT, 1718±75/mm 2 ; ERαKO BMT, 1107±48/mm 2 ; ERβKO BMT, 1567±50/mm 2 ). ERα mRNA was expressed more abundantly on EPCs compared with ERβ. Moreover, vascular endothelial growth factor was significantly downregulated on ERαKO EPCs compared with WT EPCs both in vitro and in vivo. Conclusions— Both ERα and ERβ contribute to E 2 -mediated EPC activation and tissue incorporation and to preservation of cardiac function after myocardial infarction. ERα plays a more prominent role in this process. Moreover, ERα contributes to upregulation of vascular endothelial growth factor, revealing possible mechanisms of an effect of E 2 on EPC biology. Finally, these data provide additional evidence of the importance of bone marrow–derived EPC phenotype in ischemic tissue repair.