Vascular permeability effect of adenovirus-mediated vascular endothelial growth factor gene transfer to the rabbit and rat skeletal muscle

Objective: Vascular endothelial growth factor has been used in preclinical studies and phase 1 and 2 clinical trials as a potent mediator of therapeutic angiogenesis; however, its ability to enhance the vascular permeability may be a source of potential complications. The objective of this work was to evaluate the effects of the intramuscular injection of an adenovirus vector coding for the 121-amino acid form of vascular endothelial growth factor (Ad.VEGF(121)) on vascular permeability and edema development in rabbits and rats. Methods: Different concentrations of Ad.VEGF(121) ranging from 10(5) to 10(10) plaque-forming units/mL (3 x 10(6)-3 x 10(11) particles/mL) were injected into hind limb or forelimb muscles of Wistar rats or rabbits. The size of the scrotum, the circumferences of limbs, and the concentration of vascular endothelial growth factor in the serum were measured daily after injection. Results: The injection of different concentrations of Ad.VEGF(121) into the hind limb muscles of rabbits led to a dose-dependent scrotal edema in rabbits at concentrations higher than 107 plaque-forming units/mL (P = .002). The edema developed slowly, reached its maximum level 6 days after the injection, and spontaneously resolved thereafter. At concentrations higher than 10(9) plaque-forming units/mL the scrotal edema was accompanied by skin necrosis (P = .0001). No scrotal edema was observed in rats. Conclusions: The massive species-specific scrotal edema accompanied by skin ulceration and necrosis was observed only in rabbits treated with Ad.VEGF(121) in concentrations exceeding therapeutic doses. The therapeutic doses of Ad.VEGF(121) resulted in only moderate transient scrotal edema in rabbits, suggesting that the potential for side effects of vascular endothelial growth factor therapy as a result of increased vascular permeability should not be very alarming for generally healthy patients and may not cause a significant clinical problem in the treatment of peripheral vascular diseases.