Molecular mechanisms of hypoxia-induced angiogenesis

Tissues respond to hypoxia with several compensatory mechanisms to maintain a microenvironment in which the cells can survive. These compensatory mechanisms include the formation of new blood vessels from preexisting vessels, a process termed angiogenesis, which restores the reduced oxygen supply. Hypoxia-induced angiogenesis plays an important role in physiological and pathological situations such as embryogenesis, diabetic retinopathy, and solid tumor growth. Increasing evidence suggests that upregulation of the expression of vascular endothelial growth factor (VEGF) is a key step in hypoxia-induced angiogenesis. Investigation into this hypoxic induction of VEGF should therefore lead to elucidation of the molecular mechanisms involved in hypoxia-induced angiogenesis. Using C6 glioma cells, which generate a highly vascularized glioma in vivo, the nuclear run-on assay and determination of mRNA half-life demonstrate that hypoxic induction of VEGF is the result of both transcriptional activation and increased mRNA stability. Reporter gene studies revealed that the hypoxia-responsive transcription-activating element was present in the 5'-flanking region of the VEGF gene. This element contains a consensus binding site for hypoxia-inducible factor-1 (HIF-1), which was originally found to bind the hypoxia-responsive enhancer sequence in the erythropoietin gene.