A phosphodiesterase-5 inhibitor vardenafil enhances angiogenesis through a protein kinase G-dependent hypoxia-inducible factor-1/vascular endothelial growth factor pathway.

Abstract

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.

CONCLUSIONS:

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.

• Authors: Makoto Sahara, Masataka Sata, Toshihiro Morita, Toshiaki Nakajima, Yasunobu Hirata, Ryozo Nagai
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 7 Pg. 1315-24 (Jul 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20413734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Imidazoles
• Phosphodiesterase 5 Inhibitors
• Phosphodiesterase Inhibitors
• Piperazines
• Sulfones
• Triazines
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Green Fluorescent Proteins
• Vardenafil Dihydrochloride
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Cyclic GMP-Dependent Protein Kinases
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Pde5a protein, mouse
• Cyclic GMP

Topics

• Angiogenesis Inducing Agents (pharmacology)
• Animals
• Capillaries (drug effects, enzymology, physiopathology)
• Cell Hypoxia
• Cell Movement (drug effects)
• Cells, Cultured
• Collateral Circulation (drug effects)
• Cyclic GMP (metabolism)
• Cyclic GMP-Dependent Protein Kinases (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 5 (metabolism)
• Disease Models, Animal
• Endothelial Cells (drug effects, metabolism)
• Green Fluorescent Proteins (biosynthesis, genetics)
• Hindlimb
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Imidazoles (pharmacology)
• Ischemia (drug therapy, enzymology, physiopathology)
• Male
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Muscle, Skeletal (blood supply)
• Neovascularization, Physiologic (drug effects)
• Nitric Oxide Synthase Type III (deficiency, genetics)
• Phosphodiesterase 5 Inhibitors
• Phosphodiesterase Inhibitors (pharmacology)
• Piperazines (pharmacology)
• RNA Interference
• Recovery of Function
• Regional Blood Flow (drug effects)
• Signal Transduction
• Stem Cells (drug effects, metabolism)
• Sulfones (pharmacology)
• Time Factors
• Transfection
• Triazines (pharmacology)
• Vardenafil Dihydrochloride
• Vascular Endothelial Growth Factor A (genetics, metabolism)