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A hypoxic inducible factor‐1α hybrid enhances collateral development and reduces vascular leakage in diabetic rats
Author(s) -
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
Publication year - 2009
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1318
Subject(s) - evans blue , vascular endothelial growth factor , medicine , endocrinology , hindlimb , ischemia , diabetes mellitus , vegf receptors
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‐1α hybrid (Ad2/HIF‐1α/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‐1α/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‐1α/VP16 enhanced collateral development and reduced vascular leakage in the ischemic hindlimb of ZDF rats indicating that hybrid HIF‐1α angiogenic therapy may be efficacious for peripheral vascular disease with a diabetic comorbidity. Copyright © 2009 John Wiley & Sons, Ltd.