Adenovirus-mediated VEGF₁₂₁ gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia

Background - Administration of angiogenic factors stimulates neovascularization in ischemic tissues. However, there is no evidence that angiogenesis can be induced in normoperfused skeletal muscles. We tested the hypothesis that adenovirus-mediated intramuscular (IM) gene transfer of the 121-amino-acid form of vascular endothelial growth factor (AdCMV.VEGF₁₂₁) could stimulate neovascularization in nonischemic skeletal muscle and consequently attenuate the hemodynamic deficit secondary to surgically induced ischemia. Methods and Results - Rabbits and rats received IM injections of AdCMV.VEGF₁₂₁, AdCMV.Null or saline in the thigh, 4 weeks (rabbits) or 2 weeks (rats) before femoral artery removal in the injected limb. In unoperated rats, at the site of injection of AdCMV.VEGF₁₂₁, we found 96% and 29% increases in length density of arterioles and capillaries, respectively. Increased tissue perfusion (TP) to the ischemic limb in the AdCMV.VEGF₁₂₁ group was documented, as early as day 1 after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF₁₂₁ = 5.69 ± 0.40, AdCMV.Null = 2.97 ± 0.50 and saline = 2.78 ± 0.43 mL · min^-1 · 100 g^-1 P < 0.001), more angiographically recognizable collateral vessels (angioscore) (AdCMV.VEGF₁₂₁ = 50.58 ± 1.48, AdCMV.Null = 29.08 ± 4.22, saline = 11.83 ± 1.90, P < 0.0001) and improvement of the bioenergetic reserve of the gastrocnemius muscle as assessed by ³¹P NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF₁₂₁ group persisted until it was equalized by spontaneous collateral vessel development in. untreated animals. Conclusions - IM administration of AdCMV.VEGF₁₂₁ stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia.