Department of Pharmacology, Kitasato University School of Medicine, Kitasato, Sagamihara 228-8555, Japan.
J Pharmacol Sci. 2010;112(2):167-75. doi: 10.1254/jphs.09262fp. Epub 2010 Feb 4.
Erythropoietin (EPO) has been shown to enhance angiogenesis, but its precise mechanisms of enhancement during ischemia are not fully elucidated. We examined the effect of EPO on blood flow recovery from acute hind-limb ischemia induced by ligation of the femoral artery in male C57Bl/6 mice. The density of microvessels with platelet adhesion in ischemic tissues was assessed by intravital microscopy. Treatment with EPO (100 and 1000 IU/kg, i.p.) restored blood flow in a dose-dependent manner and increased plasma levels of soluble-P-selectin, vascular endothelial growth factor (VEGF), and stromal cell-derived factor (SDF-1). Flow cytometric analysis revealed increased P-selectin expression on platelets in EPO-treated mice compared to PBS-treated mice. Intravital microscopic studies showed that EPO increased density of microvessels with platelet adhesion selectively in the ischemic tissues. Neutralizing antibody against P-selectin reduced the density of microvessels with platelet adhesion enhanced with EPO and impaired blood flow recovery with reductions in VEGF and SDF-1 levels. These results suggest that EPO administration enhances recovery from hind-limb ischemia, and platelet adhesion to the microvessels is a key event to enhance the angiogenesis in the ischemic tissues.
促红细胞生成素 (EPO) 已被证明可促进血管生成，但在缺血期间其增强作用的确切机制尚未完全阐明。我们研究了 EPO 对雄性 C57Bl/6 小鼠股动脉结扎引起的急性后肢缺血血流恢复的影响。通过活体显微镜评估血小板黏附的微血管密度。EPO（100 和 1000 IU/kg，腹腔内注射）治疗以剂量依赖的方式恢复血流，并增加血浆可溶性 P-选择素、血管内皮生长因子 (VEGF) 和基质细胞衍生因子 (SDF-1) 水平。流式细胞术分析显示，与 PBS 处理的小鼠相比，EPO 处理的小鼠血小板上 P-选择素表达增加。活体显微镜研究表明，EPO 选择性增加缺血组织中血小板黏附的微血管密度。针对 P-选择素的中和抗体减少了 EPO 增强的血小板黏附的微血管密度，并损害了血流恢复，同时降低了 VEGF 和 SDF-1 水平。这些结果表明，EPO 给药可增强后肢缺血的恢复，而血小板黏附到微血管是增强缺血组织血管生成的关键事件。
