Regulation of vascular endothelial growth factor synthesis by nitric oxide: facts and controversies

Vascular endothelial growth factor (VEGF) is the major molecule governing angiogenesis, defined as the growth of blood vessels from vascular structure. There is abundant evidence that nitric oxide (NO) is an effector molecule mediating the activity of VEGF. By binding to its receptors, VEGF initiates the signaling cascades leading to NO production and angiogenic activation of endothelial cells. Recent data show that NO induces VEGF synthesis in numerous cell types, including vascular smooth muscle cells, macrophages, keratinocytes, and tumor cells. NO enhances VEGF production by augmenting its expression through activation of Akt kinase, followed by induction of several transcription factors, of which stabilization of hypoxia-inducible factor (HIF-1) is the critical step. With respect to its effect on VEGF expression, NO mimics hypoxia, the classical activator of HIF-1 and VEGF synthesis. The effect of NO on VEGF production is also mediated by heme oxygenase, an enzyme generating carbon monoxide, which appears to stimulate VEGF release. In this review, we attempt to elucidate the molecular mechanisms underlying the effects of NO on VEGF synthesis. We also discuss some discrepant data and suggest explanations for various aspects of the NO-VEGF relationship.