The angiogenic effect of Vascular Endothelial Grows Factor (VEGF) was reported both in vitro and in vivo studies. The objectives of this year projects were (1) to conduct preclinical animal trail of efficacy of adenovirus vector encoding for recombinant secreted form of VEGF121 in stimulating an angiogenesis in the ischemic tissue;(2) to conduct an animal biosafety study of the AdCMV.VEGF121; and (3) the evaluate the angiogenic property of VEGF121 in the absence of the tissue ischemia, i.e. to test whether AdCMV.VEGF121 used prophylactically in normoperfused tissue promotes angiogenesis after induction of ischemia. The angiogenic effect of AdCMV.VEGF121 was assessed by calf blood pressure ratio (BPR) between ischemic and intact hindlimbs (rabbits), by measuring resting blood flow (RBF) to the muscles of both limbs with radioactive microspheres (rabbits), and by assessing the bioenergetic profile of the muscles during their activation using 31P NMR (rats). The biosafety was evaluated by assessing the dose-response and area of application response of VEGF121 on vascular permeability and overexpression. Prophylactic use of AdCMV.VEGF121 resulted in improved tissue blood flow as early as 1 day after induction of the hindlimb ischemia. The accelerated recovery of the tissue blood flow lasted up to 4 weeks. The therapeutic effect of AdCMV.VEGF121 was observed at concentration of 10in6 and 10in8 power of pfu/ml as measured by RBF and at concentration of 10in8 power of pfu/ml as measured by BPR. Therapeutic doses of AdCMV.VEGF121 resulted in overexpression of the VEGF121 in the blood during 24 hrs after injection and moderate, spontaneously resolved, local and scrotal edema on the sixth day after treatment. The effect of VEGF121 on vascular permeability was species- dependent - it was much higher in rabbits than in rats. - therapeutic angiogenesis, gene therapy, ischemia, blood vesels, endothelial growth factors, blood flow, animal models, rats, rabbits
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