A Phosphodiesterase-5 Inhibitor Vardenafil Enhances Angiogenesis Through a Protein Kinase G-Dependent Hypoxia-Inducible Factor-1/Vascular Endothelial Growth Factor Pathway

M. Sahara, M. Sata, T. Morita, T. Nakajima, Y. Hirata, R. Nagai
2010 Arteriosclerosis, Thrombosis and Vascular Biology  
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
more » ... schemic/nonischemic leg: 0.52Ϯ0.17 [vehicle] versus 0.92Ϯ0.09 [vardenafil], PϽ0.01). Vardenafil upregulated protein expression of vascular endothelial growth factor and hypoxia-inducible factor (HIF)-1␣ 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.)
doi:10.1161/atvbaha.109.201327 pmid:20413734 fatcat:2m46snaddzf3dgloci33ftrsse