Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice
Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice
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DOI：
10.1161/01.res.0000260179.43672.fe
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发表时间：
2007-03-16
影响因子：
20.1
通讯作者：
Shimokawa, Hiroaki
中科院分区：
文献类型：
--
作者：
Nakano, Makoto;Satoh, Kimio;Shimokawa, Hiroaki
我们最近证明内源性促红细胞生成素(Epo)/Epo受体（EpoR）系统在缺氧诱导的肺动脉高压中起重要的保护作用。然而，血管EpoR系统是否在缺血反应中参与血管生成仍有待研究。除了红细胞系细胞外，我们检测了大多数器官（包括心血管系统）缺乏EpoR（-/-）的小鼠的血管生成。与野生型（WT）小鼠相比，EpoR（-/-）拯救小鼠在股动脉结扎2周后血流量恢复、VEGF/VEGF受体系统激活和内皮祖细胞动员均受损。EpoR（-/-）修复小鼠骨髓移植WT-BM细胞可部分改善后肢缺血后血流恢复。即使用WT-BM细胞重建脑梗死，EpoR（-/-）拯救小鼠的缺血组织中VEGF的上调程度和脑梗死来源细胞的数量也明显少于WT小鼠。同样，与受体WT小鼠相比，移植WT- bm或EpoR(-/-)-拯救bm的受体EpoR(-/-)-拯救小鼠的血流恢复明显受损。此外，Matrigel植入实验和主动脉环实验显示，与WT小鼠相比，EpoR（-/-）拯救小鼠的体外微血管生长明显减少。这些结果表明，血管EpoR系统也通过上调VEGF/VEGF受体系统在后肢缺血后的血管生成中发挥重要作用，其直接途径是增强新生血管形成，间接途径是募集内皮祖细胞和脑梗死源性血管生成前细胞。
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.