In vivo enhancement of angiogenesis by adenoviral transfer of HIF-1α-modified endothelial progenitor cells (Ad-HIF-1α-modified EPC for angiogenesis)

Hypoxia inducible factor (HIF)-1 alpha over-expression may have beneficial effects in cell therapy of hypoxia-induced pathophysiological processes, such as ischemic disease. Our previous study showed the feasibility of ex vivo modification of endothelial progenitor cells (EPCs) by HIF-1 alpha transfection. In this study, we sought to determine if such ex vivo modified EPCs facilitated functional therapeutic neovascularization. Ad-HIF-1 alpha was transduced inhuman EPC in vitro. HIF-1 alpha-transduced EPCs were administered to nude mice with hind limb ischemia. BrdU-labeling of these EPCs showed that they enhanced neovascularization in vivo. Limb and toe necrosis was significantly reduced in HIF-1 alpha-EPC group compared to GFP-EPC group and medium control group at 14 days after transplantation (both P < 0.05). A statistically significant difference was still observed in the HIF-1 alpha group until 1 and 2 months of follow-up. Neovascularization was improved by both histological and physiological assessments. Exogenous EPC homing was observed. HIF-to over-expression enhanced its mRNA and protein expression in the ischemia zone. The expression of genes downstream of HIF-1 alpha was examined to explore the possible mechanism of EPC homing. In conclusion, HIF-1 alpha-EPC gene transfer augments impaired neovascularization in experimentally induced mouse hindlimb ischemia in vivo. (c) 2008 Elsevier Ltd. All rights reserved.