Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice.

Abstract

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.

• Authors: Makoto Nakano, Kimio Satoh, Yoshihiro Fukumoto, Yoshitaka Ito, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa
• Journal: Circulation research (Circ Res) Vol. 100 Issue 5 Pg. 662-9 (Mar 16 2007) ISSN: 1524-4571 [Electronic] United States
• PMID: 17293480 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Receptors, Erythropoietin
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Cell Movement (genetics)
• Endothelium, Vascular (metabolism, pathology)
• Hindlimb (blood supply, metabolism)
• Humans
• Ischemia (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Neovascularization, Pathologic (genetics, metabolism, physiopathology)
• Receptors, Erythropoietin (physiology)
• Stem Cells (metabolism, pathology)
• Up-Regulation (genetics)
• Vascular Endothelial Growth Factor A (biosynthesis, genetics)