Document Detail

A hypoxic inducible factor-1 alpha hybrid enhances collateral development and reduces vascular leakage in diabetic rats.
MedLine Citation:
PMID:  19291676     Owner:  NLM     Status:  MEDLINE    
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 alpha hybrid (Ad2/HIF-1 alpha/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 alpha/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 alpha/VP16 enhanced collateral development and reduced vascular leakage in the ischemic hindlimb of ZDF rats indicating that hybrid HIF-1 alpha angiogenic therapy may be efficacious for peripheral vascular disease with a diabetic comorbidity.
Hidetoshi Kajiwara; Zhengyu Luo; Adam J Belanger; Akihiro Urabe; Karen A Vincent; Geoffrey Y Akita; Seng H Cheng; Seibu Mochizuki; Richard J Gregory; Canwen Jiang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The journal of gene medicine     Volume:  11     ISSN:  1521-2254     ISO Abbreviation:  J Gene Med     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-04-27     Completed Date:  2009-07-24     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9815764     Medline TA:  J Gene Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  390-400     Citation Subset:  IM    
Copyright Information:
(c) 2009 John Wiley & Sons, Ltd.
Genzyme Corporation, Framingham, MA 01701-9322, USA.
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MeSH Terms
Adenoviridae / genetics
Blood Vessels / pathology*
Body Weight
Collateral Circulation / physiology*
DNA / genetics
Diabetes Mellitus, Experimental / physiopathology*
Femoral Artery / surgery
Gene Expression Regulation
Gene Transfer Techniques
Genetic Vectors / genetics
Hemoglobin A, Glycosylated / metabolism
Hindlimb / blood supply
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Injections, Intramuscular
Neovascularization, Physiologic / genetics
Rats, Zucker
Recombinant Proteins / metabolism*
Reg. No./Substance:
0/Hemoglobin A, Glycosylated; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Recombinant Proteins; 9007-49-2/DNA

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