Stabilization of Vascular Endothelial Growth Factor mRNA by Hypoxia-Inducible Factor 1

Abstract Hypoxia regulates expression of vascular endothelial growth factor (VEGF) by increasing its transcription and by stabilizing its mRNA. Despite the pivotal role of hypoxia-inducible factor 1 (HIF-1) in transcriptional activation of hypoxia-responsive genes, it is not known whether HIF-1 mediates hypoxia-induced stabilization of VEGF mRNA. We constructed adenoviral vectors expressing either the wild-type HIF-1α (Ad2/HIF-1α/FL), a constitutively stable hybrid form of HIF-1α (Ad2/HIF-1α/VP16), or no transgene (Ad2/CMVEV). In rat glioma (C6) cells and human cardiac, vascular smooth muscle, and endothelial cells, infection with Ad2/HIF-1α/VP16 or Ad2/HIF-1α/FL increased VEGF expression at both the mRNA and protein levels. Under normoxic conditions, the half-life of VEGF mRNA was 42 min in C6 cells. Hypoxia and Ad2/HIF-1α/VP16 increased the half-life of VEGF mRNA to 3.3 and 2.7 h, respectively, while Ad2/CMVEV had no effect. These studies are the first to demonstrate that overexpression of HIF-1α increases VEGF mRNA stability. Our results also suggest that stabilization of VEGF mRNA by hypoxia is mediated, at least in part, by HIF-1.