A hypoxic inducible factor-1a hybrid enhances collateral development and reduces vascular leakage in diabetic rats

• Published in: The journal of gene medicine 2009-05, Vol.11 (5), p.390-400
• Main Authors: Kajiwara, Hidetoshi, Luo, Zhengyu, Belanger, Adam J, Urabe, Akihiro, Vincent, Karen A, Akita, Geoffrey Y, Cheng, Seng H, Mochizuki, Seibu, Gregory, Richard J, Jiang, Canwen
• Format: Article
• Language: English
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/jgm.1318

Background Diabetes mellitus is a common comorbidity of atherosclerosis. Hypoxia-inducible factor-1 (HIF-1) is the master regulator of the angiogenic response to hypoxia. Methods We studied the effects of adenoviral vectors expressing a constitutively active HIF-1 hybrid (Ad2/HIF-1/VP16) or vascular endothelial growth factor (Ad2/VEGF) on collateral development and vascular leakiness in a diabetic rat model of hindlimb ischemia. Results After the removal of the right femoral artery, the mRNA levels of VEGF, angiopoietin-1 and angiopietin-4 in the calf muscles, as measured by Taqman reverse transcriptase-polymerase chain reaction, were transiently elevated in Zucker lean (ZL) but not Zucker diabetic fatty (ZDF) rats. The angiographic score, as determined by post-mortem angiography, was significantly lower in ZDF animals 35 days after surgery compared to their ZL counterparts. In separate animals, intramuscular injection of Ad2/HIF-1a/VP16 and Ad/2VEGF into the thigh muscles significantly increased the angiographic score and capillary density 21 and 35 days after the injection compared to Ad2/CMVEV (a vector expressing no transgene) or vehicle. After the injection of Ad2/CMVEV or vehicle, the Evans-blue dye content in the thigh muscles was significantly higher in ZDF rats than their ZL counterparts. Ad2/HIF-1/VP16 but not Ad2/VEGF reduced tissue Evans blue dye content. Conclusions The endogenous angiogenic response to ischemia was impaired in ZDF rats, possibly due to down-regulation of angiogenic factors. Ad2/HIF-1/VP16 enhanced collateral development and reduced vascular leakage in the ischemic hindlimb of ZDF rats indicating that hybrid HIF-1 angiogenic therapy may be efficacious for peripheral vascular disease with a diabetic comorbidity.