A hypoxic inducible factor-1 alpha hybrid enhances collateral development and reduces vascular leakage in diabetic rats.
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.
Kajiwara
Hidetoshi
H
Genzyme Corporation, Framingham, MA 01701-9322, USA.
Luo
Zhengyu
Z
Belanger
Adam J
AJ
Urabe
Akihiro
A
Vincent
Karen A
KA
Akita
Geoffrey Y
GY
Cheng
Seng H
SH
Mochizuki
Seibu
S
Gregory
Richard J
RJ
Jiang
Canwen
C
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001808:Blood Vessels / Q000473:pathology*; D001835:Body Weight; D003097:Collateral Circulation / Q000502:physiology*; D004247:DNA / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005263:Femoral Artery / Q000601:surgery; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006442:Glycated Hemoglobin / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D007511:Ischemia; D018919:Neovascularization, Physiologic / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D011994:Recombinant Proteins / Q000378:metabolism*; D019076:Transgenes
D004247:DNA; D006442:Glycated Hemoglobin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011994:Recombinant Proteins