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(Circulation. 2001;104:753.)
© 2001 American Heart Association, Inc.

Brief Rapid Communications

Adenovirus-Mediated Gene Transfer of VEGF₁₂₁ Improves Lower-Extremity Endothelial Function and Flow Reserve

Sanjay Rajagopalan, MD; Manan Shah, BS; Ann Luciano, RN; Ronald Crystal, MD; Elizabeth G. Nabel, MD

From the Department of Internal Medicine, University of Michigan, Ann Arbor (S.R., M.S., A.L.), the National Institutes of Health, Bethesda, Md (E.G.N.), and New York Presbyterian Hospital—Weil Medical College, Cornell University, New York, NY (R.C.).

Correspondence to Sanjay Rajagopalan, MD, Division of Cardiology, Section of Vascular Medicine, L3119 Women’s Hospital, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0273. E-mail srajagop{at}umich.edu

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_GVVEGF_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.

Methods and Results— Blood flow to the index extremity was measured by thermodilution at baseline and 30 days after administration of Ad_GVVEGF_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_GVVEGF_121.10. In response to acetylcholine (150 µg/min and 300 µg/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_GVVEGF_121.10 treatment. After Ad_GVVEGF_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_GVVEGF_121.10 treatment versus after Ad_GVVEGF_121.10 for both doses). Infusion of nitroglycerin resulted in a 1.8-fold increase in flow before Ad_GVVEGF_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_GVVEGF_121.10 (P=NS before Ad_GVVEGF_121.10 versus after Ad_GVVEGF_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.

Key Words: gene therapy • angiogenesis • growth substances • endothelium • nitric oxide

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