Adenovirus-mediated gene transfer of VEGF(121) improves lower-extremity endothelial function and flow reserve.
BACKGROUND
Vascular endothelial growth factor (VEGF) currently is being evaluated in clinical angiogenesis trials involving patients with peripheral arterial disease. We hypothesized that delivery of VEGF to the skeletal muscle of the lower extremity using an adenoviral vector (Ad(GV)VEGF(121.10)) would improve peripheral endothelial function. Accordingly, we investigated lower-extremity endothelial function in patients enrolled in a Phase I adenovirus-mediated gene delivery trial of VEGF(121.10).


RESULTS
Blood flow to the index extremity was measured by thermodilution at baseline and 30 days after administration of Ad(GV)VEGF(121.10), in response to the infusion of endothelium-dependent and -independent agonists (acetylcholine and nitroglycerin, respectively) into the ipsilateral femoral artery. There was no difference in basal flow before or after treatment with Ad(GV)VEGF(121.10). In response to acetylcholine (150 microg/min and 300 microg/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/min) change in flow before Ad(GV)VEGF(121.10) treatment. After Ad(GV)VEGF(121.10) treatment, flow increased 2.4-fold (0.310+/-0.04 to 0.730+/-0.10 L/min) and 2.3-fold (0.31+/-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 increase (0.31+/-0.04 to 0.73+/-0.09 L/min) after Ad(GV)VEGF(121.10) (P=NS before Ad(GV)VEGF(121.10) versus after Ad(GV)VEGF(121.10)). Lower-extremity flow reserve increased in all patients in response to at least 1 dose of acetylcholine. Peak walking times increased concomitant with improvement in endothelial function.


CONCLUSIONS
Adenoviral gene transfer of VEGF(121.10) appears to modulate endothelial function and lower-extremity flow reserve in patients with peripheral arterial disease.
Rajagopalan
S
S
Department of Internal Medicine, University of Michigan, Ann Arbor, USA. srajagop@umich.edu
Shah
M
M
Luciano
A
A
Crystal
R
R
Nabel
E G
EG
D000109:Acetylcholine / Q000008:administration & dosage; D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D003875:Drug Eruptions / Q000209:etiology; D004487:Edema / Q000209:etiology; D016228:Endothelial Growth Factors / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects; D005263:Femoral Artery; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects / Q000502:physiology; D006801:Humans; D007261:Infusions, Intra-Arterial; D007273:Injections, Intramuscular; D007866:Leg / Q000098:blood supply / Q000503:physiopathology; D008222:Lymphokines / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D005996:Nitroglycerin / Q000008:administration & dosage; D016491:Peripheral Vascular Diseases / Q000503:physiopathology / Q000628:therapy*; D012039:Regional Blood Flow / Q000187:drug effects; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005996:Nitroglycerin; D000109:Acetylcholine