Figure 2

Molecular mechanisms of hypoxia-induced angiogenesis. Under normoxic conditions (panel A), HIF-1α is hydroxylated by the active prolyl-4-hydroxylase enzyme, which facilitates the binding of VHL protein and leads to rapid HIF-1α degradation by the ubiquitin proteasome system. In the face of hypoxia (panel B), the hydroxylase enzyme is inactive and HIF-1α is stabilized in its de-hydroxylated state. The stable HIF-1α translocates to the nucleus, where it accumulates and dimerizes with the constitutively expressed HIF-1β, forming the intact HIF-1 complex. This complex binds hypoxia response elements (HREs) in selective genes to alter transcriptional activity. A notable hypoxia-induced gene is that coding for vascular endothelial growth factor (VEGF), a cytokine which potently stimulates neoangiogenesis [24].