Regulation of hypoxia inducible factor-1 by nitric oxide in contrast to hypoxia in microvascular endothelium.

Hypoxia activates the transcription factor, hypoxia inducible factor-1 (HIF-1). Besides hypoxia, HIF-1 can be activated under normoxic conditions by nitric oxide. The signal transduction pathways involved in HIF-1alpha stabilization, HIF-1 DNA binding and transactivation by NO and hypoxia in microvascular endothelium remains unknown. We report that protein phosphorylation is involved in HIF-1 activation during hypoxia and NO. The phosphatidylinositol 3-kinase (PI-3K)/Akt pathway has differential effects on HIF-1 activation by hypoxia and NO. Our data indicate that the PI-3K/Akt pathway is insufficient for HIF-1alpha induction by hypoxia. The lipid and protein phosphatase activities of PTEN also appear to be involved in regulation of HIF-1alpha by NO.