Published online before print February 9, 2007, doi: 10.1161/01.RES.0000260179.43672.fe
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Submitted on August 2, 2006
Revised on December 19, 2006
Accepted on January 25, 2007
Important Role of Erythropoietin Receptor to Promote VEGF Expression and Angiogenesis in Peripheral Ischemia in Mice
Makoto Nakano ;
From the From the Departments of Cardiovascular Medicine (MN, KS, YF, YI, YK, HS) and Microbiology and Immunology (NI, KS), Tohoku University Graduate School of Medicine, Sendai, Japan.
* To whom correspondence should be addressed. E-mail: fukumoto{at}cardio.med.tohoku.ac.jp.
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/or BM-derived proangiogenic cells.
Key words: angiogenesis • ischemia • progenitor cells • VEGF • erythropoietin
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