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

Authors :
Kajiwara H
Luo Z
Belanger AJ
Urabe A
Vincent KA
Akita GY
Cheng SH
Mochizuki S
Gregory RJ
Jiang C
Source :
The journal of gene medicine [J Gene Med] 2009 May; Vol. 11 (5), pp. 390-400.
Publication Year :
2009

Abstract

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.<br />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.<br />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.<br />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.<br /> ((c) 2009 John Wiley & Sons, Ltd.)

Details

Language :
English
ISSN :
1521-2254
Volume :
11
Issue :
5
Database :
MEDLINE
Journal :
The journal of gene medicine
Publication Type :
Academic Journal
Accession number :
19291676
Full Text :
https://doi.org/10.1002/jgm.1318