Effects of VEGF(121) and/or VEGF(165) gene transfection on collateral circulation development

Background and purpose: Angiogenesis is regulated by various factors, inclu ding vascular endothelial growth factor (VEGF). Five isoforms of VEGF have been discovered: VEGF(121), VEGF(115), VEGF(165), VEGF(189), and VEGF(206). The teleologic basis for the various VEGF isoforms remains unclear, but di fferent VEGF isoforms may mediate distinct endothelial cell functions such as angiogenesis, vascular permeability, and differentiation. We sought to d etermine the effects of various VEGF isoforms on angiogenesis under ischemi c conditions in rabbits. Methods: The effects of VEGF(121) and/or VEGF(165) gene transfection on col lateral circulation development in ischemic rabbit hindlimb muscles were in vestigated by using naked plasmids encoding: VEGF(121) or VEGF(165) (pVEGF( 121) or pVEGF(165)), either individually or in combination. pCMV beta was u sed as the control plasmid. The femoral artery on one side of New Zealand W hite rabbits was ligated. Ten days later, the ischemic muscles received dir ect intramuscular injection of pVEGF(121) (500 mu g). pVEGF(165) (500 mu g) , or pVEGF(121) (250 mu g) + pVEGF(165) (250 mu g) in experimental groups, while pCMV beta (500 mu g) was used in the control group. Therapeutic effec ts were evaluated 30 days later by anatomic and physiologic analysis. Results: Internal iliac angiography showed strong development of collateral circulation in all of the pVEGF-treated groups. In contrast, collateral ar teries developed weakly in the control group. Combination treatment with bo th pVEGF(121) and pVEGF(165) did not result in additional improvement compa red with pVEGF(121) or pVEGF(165) treatment alone (angiographic scores: pVE GF(121) = 0.85 +/- 0.10; pVEGF(165) = 0.81 +/- 0.11; pVEGF(121) + pVEGF(165 ) = 0.83 +/- 0.09; control = 0.53 +/- 0.09; p < 0.01). A favorable response in the development of circulation at the capillary level with pVEGF(121) a nd/or pVEGF(165) versus pCMV beta was also found. Blood. pressure measureme nt and regional blood flow measurement using colored microspheres revealed similar results. Conclusions: Our results show that direct intramuscular injection of naked DNA encoding VEGF(121) or VEGF(165), individually or in combination, is an effective method for gene transfer in an animal model of ischemic limbs and results in augmented collateral vascular development and tissue perfusion.