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The vasodilator hydralazine, used clinically in cardiovascular therapy, relaxes arterial smooth muscle by inhibiting accumulation of intracellular free Ca2+ via an unidentified primary target. Collagen prolyl hydroxylase is a known target of hydralazine. We therefore investigated whether inhibition of other members of this enzyme family, namely the hypoxia-inducible factor (HIF)-regulating O2-dependent prolyl hydroxylase domain (PHD) enzymes, could represent a novel mechanism of action. Hydralazine induced rapid and transient expression of HIF-1alpha and downstream targets of HIF (endothelin-1, adrenomedullin, haem oxygenase 1, and vascular endothelial growth factor [VEGF]) in endothelial and smooth muscle cells and induced endothelial cell-specific proliferation. Hydralazine dose-dependently inhibited PHD activity and induced nonhydroxylated HIF-1alpha, evidence for HIF stabilization specifically by inhibition of PHD enzyme activity. In vivo, hydralazine induced HIF-1alpha and VEGF protein in tissue extracts and elevated plasma VEGF levels. In sponge angiogenesis assays, hydralazine increased stromal cell infiltration and blood vessel density versus control animals. Thus, hydralazine activates the HIF pathway through inhibition of PHD activity and initiates a pro-angiogenic phenotype. This represents a novel mechanism of action for hydralazine and presents HIF as a potential target for treatment of ischemic disease.

Original publication

DOI

10.1161/01.res.0000134924.89412.70

Type

Journal article

Journal

Circulation research

Publication Date

07/2004

Volume

95

Pages

162 - 169

Addresses

Cancer Research UK Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.

Keywords

Cells, Cultured, Cell Line, Tumor, Endothelial Cells, Myocytes, Smooth Muscle, Animals, Mice, Inbred BALB C, Mice, Inbred C57BL, Humans, Mice, Mice, Nude, Carcinoma, Carcinoma, Renal Cell, Breast Neoplasms, Kidney Neoplasms, Hydralazine, Heme Oxygenase (Decyclizing), Procollagen-Proline Dioxygenase, Vascular Endothelial Growth Factor A, Peptides, Endothelin-1, DNA-Binding Proteins, Membrane Proteins, Nuclear Proteins, Transcription Factors, Vasodilator Agents, Enzyme Inhibitors, Angiogenesis Inducing Agents, Implants, Experimental, Cell Hypoxia, Gene Expression Regulation, Neovascularization, Physiologic, Dose-Response Relationship, Drug, Heme Oxygenase-1, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Adrenomedullin