Mutant hypoxia inducible factor-1 alpha improves angiogenesis and tissue perfusion in ischemic rabbit skeletal muscle

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is one of the most potent angiogenic growth factors. It regulates genes involved in angiogenesis, but is inactivated rapidly by normoxia. Ad-HIF-1 alpha-Trip was constructed by transforming Pro402, Pro564, and Asn803 in HIF-1 alpha to alanine in order to delay degradation and create a constitutive transcriptional activator. In this study, we investigated whether Ad-HIF-1 alpha-Trip could induce functional mature angiogenesis and the possible mechanisms involved. We found that Ad-HIF-1 alpha-Trip increased the expression of multiple angiogenic genes in cultured HMVEC-Ls, including VEGF, PLGF, PAI-1, and PDGF. In a rabbit model of acute hind limb ischemia, Ad-HIF-1 alpha-Trip improved tissue perfusion and collateral vessels, as measured by contrast-enhanced ultrasound (CEU), CT angiography, and vascular casting. Ad-HIF-1 alpha-Trip also produced more histologically identifiable capillaries, which were verified by immunostaining, compared with controls. Interestingly, inhibition of CBP/p300 by curcumin prevented HIF-1 alpha from inducing the expression of several angiogenic genes. The present study suggests that Ad-HIF-1 alpha-Trip can induce mature angiogenesis and improve tissue perfusion in ischemic rabbit skeletal muscle. CBP/p300, which interacts with the transactivation domains of HIF-1 alpha, is important for HIF-1 alpha-induced transcription of angiogenic genes. (C) 2010 Elsevier Inc. All rights reserved.