Urokinase gene transfer augments angiogenesis in ischemic skeletal and myocardial muscle.
Urokinase plasminogen activator (uPA) is required for both endogenous and vascular endothelial growth factor (VEGF)-augmented angiogenesis in normal tissues, leading us to hypothesize that uPA augmentation by gene transfer might promote angiogenesis in ischemic tissues. Overexpression of uPA was studied in rat myocardial infarction (MI) and mouse hind limb ischemia models and compared with VEGF overexpression effects. Animals were divided into control and three experimental groups (n = 6), receiving intramuscular injections of plasmids as follows: (i) control (empty vector or expressing beta-galactosidase); (ii) uPA; (iii) VEGF(165); (iv) a 1:1 mixture of uPA and VEGF(165). The capillary densities in both ischemic models were greater (P < 0.05) in tissues treated with uPA, VEGF, or a combination of both than in controls. Infarct size was reduced in hearts from uPA and VEGF experimental groups compared with controls (P < 0.05). Local overexpression of uPA induced a marked increase in the number of macrophages and myofibroblasts present within infarcts. Hind limb blood flow was greater in all experimental groups by day 10 (P < 0.05). Overall, the effects of uPA and VEGF were uniformly comparable. Additional analysis revealed association of local edema with VEGF but not with uPA treatment. This study established that uPA gene therapy effectively induces functionally significant angiogenesis in models of acute MI and hind limb ischemia.
Traktuev
Dmitry O
DO
Indiana Center for Vascular Biology and Medicine, Indiana University, Indianapolis, Indiana, USA.
Tsokolaeva
Zoya I
ZI
Shevelev
Alexander A
AA
Talitskiy
Konstantin A
KA
Stepanova
Victoria V
VV
Johnstone
Brian H
BH
Rahmat-Zade
Tahmina M
TM
Kapustin
Alexander N
AN
Tkachuk
Vsevolod A
VA
March
Keith L
KL
Parfyonova
Yelena V
YV
D000818:Animals; D001835:Body Weight; D002465:Cell Movement; D015870:Gene Expression; D015316:Genetic Therapy; D006614:Hindlimb / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D051379:Mice; D023421:Models, Animal; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D010957:Plasmids / Q000235:genetics; D051381:Rats; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014568:Urokinase-Type Plasminogen Activator