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Evaluation of angiogenesis and side effects in ischemic rabbit hindlimbs after intramuscular injection of adenoviral vectors encoding VEGF and LacZ
Author(s) -
Vajanto Ismo,
Rissanen Tuomas T.,
Rutanen Juha,
Hiltunen Mikko O.,
Tuomisto Tiina T.,
Arve Katja,
Närvänen Outi,
Manninen Hannu,
Räsänen Heikki,
Hippeläinen Mikko,
Alhava Esko,
YläHerttuala Seppo
Publication year - 2002
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.287
Subject(s) - genetic enhancement , angiogenesis , vascular endothelial growth factor , intramuscular injection , therapeutic angiogenesis , transgene , medicine , hindlimb , biology , pathology , endocrinology , andrology , neovascularization , gene , vegf receptors , biochemistry
Background Recent studies have suggested the therapeutic potential of vascular endothelial growth factor (VEGF) gene therapy in ischemic skeletal muscle. However, only limited information is available about the effects of VEGF gene therapy in different regions of ischemic limbs, effects of control adenoviruses, and biodistribution of the transgenes after intramuscular (i.m.) administration. Here we studied angiogenesis and side effects of adenovirus‐mediated VEGF and β‐galactosidase (LacZ) gene transfers in ischemic rabbit hindlimbs. Methods and results Ten days after induction of ischemia, rabbits were treated with i.m. injections of saline, LacZ adenovirus (Ad Lac Z; 2×10 10 pfu) or adenovirus encoding mouse VEGF 164 (AdVEGF; 2×10 10 pfu). In rabbits treated with AdVEGF an increase in serum VEGF 164 levels was detected by ELISA three and seven days after the gene transfer. 30 days after the gene transfer a positive effect on capillary density was observed in the thigh region both in rabbits treated with AdVEGF and Ad Lac Z compared with animals that received saline. On the other hand, AdVEGF and Ad Lac Z gene transfers had no effect on the capillary density in the calf region on day 30. A positive correlation between the capillary density and the number of collateral arteries was observed in the thigh. Hindlimb and testis edema and excess non‐physiological growth of capillaries were detected as adverse effects of the AdVEGF gene therapy. Biodistribution analysis showed that the transgene was present not only in the target muscle, but also in ectopic tissues seven days after i.m. gene transfer. Conclusions The results suggest that a high dose of adenoviral vector encoding either AdVEGF or Ad Lac Z induces angiogenesis in the rabbit hindlimb ischemia model; i.m. injection of adenovirus leads to the transfection of ectopic organs; and AdVEGF gene transfer induces edema in ischemic skeletal muscle. Copyright © 2002 John Wiley & Sons, Ltd.