A Phosphodiesterase-5 Inhibitor Vardenafil Enhances Angiogenesis Through a Protein Kinase G-Dependent Hypoxia-Inducible Factor-1/Vascular Endothelial Growth Factor Pathway
A Phosphodiesterase-5 Inhibitor Vardenafil Enhances Angiogenesis Through a Protein Kinase G-Dependent Hypoxia-Inducible Factor-1/Vascular Endothelial Growth Factor Pathway
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DOI：
10.1161/atvbaha.109.201327
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发表时间：
2010-07-01
影响因子：
8.7
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Sahara, Makoto;Sata, Masataka;Nagai, Ryozo
方法和结果-单侧后肢缺血产生切除右股动脉野生型C3 H/He小鼠，无论是车辆或PDE 5抑制剂伐地那非（10毫克/公斤每天）。手术后4周，伐地那非显著增强了缺血肌肉的血流恢复和毛细血管侧支形成（缺血/非缺血腿的血流比：0.52 +/- 0.17 [载体] vs 0.92 +/- 0.09 [伐地那非]，P < 0.01）。伐地那非上调缺血肌肉中血管内皮生长因子和缺氧诱导因子（HIF）-1 α的蛋白表达，增强外周血和骨髓中Sca-1/Flk-1阳性内皮祖细胞（EPCs）的动员，促进新生血管形成。伐地那非还促进人脐静脉内皮细胞的毛细血管样管形成，并增加体外人血单核细胞来源的EPCs的数量。此外，报告基因分析表明，伐地那非和cGMP激活缺氧条件下的HIF-1的反式激活活性。伐地那非的这些作用被显着抑制内皮型一氧化氮合酶，可溶性鸟苷酸环化酶抑制剂，和蛋白激酶G抑制剂的基因消融，respectively. Conclusion-我们的研究结果表明，PDE 5抑制增强缺血诱导的血管生成动员内皮祖细胞通过蛋白激酶G-依赖HIF-1/血管内皮生长因子途径。PDE 5抑制可能具有治疗缺血性心血管疾病的治疗潜力。（Arterioscler Thromb Vasc Biol.2010; 30：1315-1324.）
Objective-We examined whether phosphodiesterase-5 (PDE5) inhibition can promote ischemia-induced angiogenesis.Methods and Results-Unilateral hindlimb ischemia was generated by resecting right femoral artery in wild-type C3H/He mice, treated with either vehicle or a PDE5 inhibitor vardenafil (10 mg/kg per day). Four weeks after surgery, vardenafil significantly enhanced blood flow recovery and augmented capillary collateral formation in ischemic muscle (blood flow ratios of ischemic/nonischemic leg: 0.52 +/- 0.17 [vehicle] versus 0.92 +/- 0.09 [vardenafil], P < 0.01). Vardenafil upregulated protein expression of vascular endothelial growth factor and hypoxia-inducible factor (HIF)-1 alpha in ischemic muscle and enhanced mobilization of Sca-1/Flk-1-positive endothelial progenitor cells (EPCs) in peripheral blood and bone marrow, contributing to neovascularization. Vardenafil also promoted capillary-like tube formation of human umbilical vein endothelial cells and increased the number of human blood mononuclear cell-derived EPCs in vitro. Furthermore, reporter assays showed that vardenafil and cGMP activated the transactivation activity of HIF-1 under hypoxia. These effects of vardenafil were markedly inhibited by genetic ablation of endothelial nitric oxide synthase, a soluble guanylate cyclase inhibitor, and a protein kinase G inhibitor, respectively.Conclusion-Our results suggest that PDE5 inhibition enhances ischemia-induced angiogenesis with mobilization of EPCs through a protein kinase G-dependent HIF-1/vascular endothelial growth factor pathway. PDE5 inhibition may have a therapeutic potential to treat ischemic cardiovascular diseases. (Arterioscler Thromb Vasc Biol. 2010; 30: 1315-1324.)