Estrogen receptors alpha and beta mediate contribution of bone marrow-derived endothelial progenitor cells to functional recovery after myocardial infarction.
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 alpha (ER alpha) and beta (ER beta) in EPC biology are largely unknown.


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 alpha-knockout mice (ER alphaKO) and moderately impaired in ER betaKO EPCs. The number of ER alphaKO EPCs (42.4+/-1.5; P<0.001) and ER betaKO 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 ER alphaKO BMT (WT mice transplanted with ER alphaKO bone marrow) (2.03+/-0.18%; P=0.004 versus WT BMT) and ER betaKO 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 ER alphaKO BMT and ER betaKO BMT compared with WT mice (WT BMT, 1718+/-75/mm2; ER alphaKO BMT, 1107+/-48/mm2; ER betaKO BMT, 1567+/-50/mm2). ER alpha mRNA was expressed more abundantly on EPCs compared with ER beta. Moreover, vascular endothelial growth factor was significantly downregulated on ER alphaKO EPCs compared with WT EPCs both in vitro and in vivo.


CONCLUSIONS
Both ER alpha and ER beta contribute to E2-mediated EPC activation and tissue incorporation and to preservation of cardiac function after myocardial infarction. ER alpha plays a more prominent role in this process. Moreover, ER alpha 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.
Hamada
Hiromichi
H
Division of Cardiovascular Research, St Elizabeth Medical Center of Boston, Tufts University School of Medicine, Boston, Mass, USA.
Kim
Myeong Kon
MK
Iwakura
Atsushi
A
Ii
Masaaki
M
Thorne
Tina
T
Qin
Gangjian
G
Asai
Jun
J
Tsutsumi
Yoshiaki
Y
Sekiguchi
Haruki
H
Silver
Marcy
M
Wecker
Andrea
A
Bord
Evelyn
E
Zhu
Yan
Y
Kishore
Raj
R
Losordo
Douglas W
DW
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000503:physiopathology*; D019650:Hematopoietic Stem Cell Mobilization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000503:physiopathology* / Q000601:surgery*; D020127:Recovery of Function; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D002316:Cardiotonic Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol