Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice.
We have recently demonstrated that endogenous erythropoietin (Epo)/Epo receptor (EpoR) system plays an important protective role in hypoxia-induced pulmonary hypertension. However, it remains to be examined whether vascular EpoR system contributes to angiogenesis in response to ischemia. We examined angiogenesis in EpoR(-/-)-rescued mice that lack EpoR in most organs including cardiovascular system except erythroid-lineage cells. Two weeks after femoral artery ligation, blood flow recovery, activation of VEGF/VEGF receptor system, and mobilization of endothelial progenitor cells were all impaired in EpoR(-/-)-rescued mice as compared with wild-type (WT) mice. Bone marrow (BM) transplantation with WT-BM cells in EpoR(-/-)-rescued mice partially but significantly improved blood flow recovery after hindlimb ischemia. The extent of VEGF upregulation and the number of BM-derived cells in ischemic tissue were significantly less in EpoR(-/-)-rescued mice compared with WT mice even after BM reconstitution with WT-BM cells. Similarly, the recovery of blood flow was significantly impaired in recipient EpoR(-/-)-rescued mice that had been transplanted with WT-BM or EpoR(-/-)-rescued-BM as compared with recipient WT mice. Furthermore, the Matrigel implantation assay and aortic ring assay showed that microvessel growth in vitro was significantly reduced in EpoR(-/-)-rescued mice as compared with WT mice. These results indicate that vascular EpoR system also plays an important role in angiogenesis in response to hindlimb ischemia through upregulation of VEGF/VEGF receptor system, both directly by enhancing neovascularization and indirectly by recruiting endothelial progenitor cells and BM-derived proangiogenic cells.
Nakano
Makoto
M
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan. fukumoto@cardio.med.tohoku.ac.jp.
Satoh
Kimio
K
Fukumoto
Yoshihiro
Y
Ito
Yoshitaka
Y
Kagaya
Yutaka
Y
Ishii
Naoto
N
Sugamura
Kazuo
K
Shimokawa
Hiroaki
H
D000818:Animals; D002465:Cell Movement / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006614:Hindlimb / Q000098:blood supply* / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D017467:Receptors, Erythropoietin / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
D017467:Receptors, Erythropoietin; D042461:Vascular Endothelial Growth Factor A