Adenovirus-mediated gene transfer of VEGF(121) improves lower-extremity endothelial function and flow reserve

Background-Vascular endothelial growth factor (VEGF) currently is being eva luated in clinical angiogenesis trials involving patients with peripheral a rterial disease. We hypothesized that delivery of VEGF to the skeletal musc le of the lower extremity using an adenoviral vector (Ad(GV)VEGF(121.10)) w ould improve peripheral endothelial function. Accordingly, we investigated lower-extremity endothelial function in patients enrolled in a Phase I aden ovirus-mediated gene delivery trial of VEGF(121.10), Methods and Results-Blood flow to the index extremity was measured by therm odilution at baseline and 30 days after administration of Ad(GV)VEGF(121.10 ), in response to the infusion of endothelium-dependent and -independent ag onists (acetylcholine and nitroglycerin, respectively) into the ipsilateral femoral artery. There was no difference in basal flow before or after trea tment with Ad(GV)VEGF(121.10). In response to acetylcholine (150 mug/min an d 300 mug/min), there was a 0.9-fold (0.33 +/- 0.03 to 0.32 +/- 0.03 L/min) and 1.2-fold (0.33 +/- 0.03 to 0.490 +/- 0.02 L/inin) change in flow befor e Ad(GV)/TGF(121.10) treatment. After Ad(GV)VEGF(121.10) treatment, flow in creased 2.4-fold (0.310 +/- 0.04 to 0.730 +/- 0.10 L/min) and 2.3-fold (0.3 1 +/- 0.04 to 0.7 +/- 0.08 L/min), respectively (P <0.05 before Ad(GV)VEGF( 121.10) treatment versus after Ad(GV)VEGF(121.10) for both doses). Infusion of nitroglycerin resulted in a 1.8-fold increase in flow before Ad(GV)VEGF (121.10) (0.33 +/- 0.03 to 0.58 +/- 0.06 L/min) compared with a 2.4-fold in crease (0.31 +/- 0.04 to 0.73 +/- 0.09 L/min) after Ad(GV)VEGF(121.10) (P=N S before Ad(GV)VEGF(121.10) versus after Ad(GV)VEGF(121.10)). Lower-extremi ty flow reserve increased in all patients in response to at least I dose of acetylcholine. Peak walking times increased concomitant with improvement i n endothelial function. Conclusions-Adenoviral gene transfer of VEGF(121.10) appears to modulate en dothelial function and lower-extremity flow reserve in patients with periph eral arterial disease.