Adenovirus-Mediated VEGF 121 Gene Transfer Stimulates Angiogenesis in Normoperfused Skeletal Muscle and Preserves Tissue Perfusion After Induction of Ischemia

Abstract

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.VEGF 121 ) 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.VEGF 121 , 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.VEGF 121 , 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.VEGF 121 group was documented, as early as day 1 after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF 121 =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.VEGF 121 =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 31 P NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF 121 group persisted until it was equalized by spontaneous collateral vessel development in untreated animals. Conclusions —IM administration of AdCMV.VEGF 121 stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia.