Tags

Type your tag names separated by a space and hit enter

A phosphodiesterase-5 inhibitor vardenafil enhances angiogenesis through a protein kinase G-dependent hypoxia-inducible factor-1/vascular endothelial growth factor pathway.
Arterioscler Thromb Vasc Biol. 2010 Jul; 30(7):1315-24.AT

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+Show Affiliations

Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. tky@umin.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20413734

Citation

Sahara, Makoto, et al. "A Phosphodiesterase-5 Inhibitor Vardenafil Enhances Angiogenesis Through a Protein Kinase G-dependent Hypoxia-inducible Factor-1/vascular Endothelial Growth Factor Pathway." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 7, 2010, pp. 1315-24.
Sahara M, Sata M, Morita T, et al. A phosphodiesterase-5 inhibitor vardenafil enhances angiogenesis through a protein kinase G-dependent hypoxia-inducible factor-1/vascular endothelial growth factor pathway. Arterioscler Thromb Vasc Biol. 2010;30(7):1315-24.
Sahara, M., Sata, M., Morita, T., Nakajima, T., Hirata, Y., & Nagai, R. (2010). A phosphodiesterase-5 inhibitor vardenafil enhances angiogenesis through a protein kinase G-dependent hypoxia-inducible factor-1/vascular endothelial growth factor pathway. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(7), 1315-24. https://doi.org/10.1161/ATVBAHA.109.201327
Sahara M, et al. A Phosphodiesterase-5 Inhibitor Vardenafil Enhances Angiogenesis Through a Protein Kinase G-dependent Hypoxia-inducible Factor-1/vascular Endothelial Growth Factor Pathway. Arterioscler Thromb Vasc Biol. 2010;30(7):1315-24. PubMed PMID: 20413734.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A phosphodiesterase-5 inhibitor vardenafil enhances angiogenesis through a protein kinase G-dependent hypoxia-inducible factor-1/vascular endothelial growth factor pathway. AU - Sahara,Makoto, AU - Sata,Masataka, AU - Morita,Toshihiro, AU - Nakajima,Toshiaki, AU - Hirata,Yasunobu, AU - Nagai,Ryozo, Y1 - 2010/04/22/ PY - 2010/4/24/entrez PY - 2010/4/24/pubmed PY - 2010/7/14/medline SP - 1315 EP - 24 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 30 IS - 7 N2 - 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/20413734/A_phosphodiesterase_5_inhibitor_vardenafil_enhances_angiogenesis_through_a_protein_kinase_G_dependent_hypoxia_inducible_factor_1/vascular_endothelial_growth_factor_pathway_ L2 - https://www.ahajournals.org/doi/10.1161/ATVBAHA.109.201327?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -