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(Stroke. 2000;31:968.)
© 2000 American Heart Association, Inc.

Original Contributions

In Vivo Gene Transfer of Endothelial Nitric Oxide Synthase to Carotid Arteries From Hypercholesterolemic Rabbits Enhances Endothelium-Dependent Relaxations

Jun’ichi Sato, MD, PhD; Tibor Mohácsi, MD; Audra Noel, MD; Corey Jost, MD; Peter Gloviczki, MD; Geza Mozes, MD, PhD; Zvonimir S. Katusic, MD, PhD Timothy O’Brien, MD, PhD

From the Departments of Endocrinology (J.S., T.O.) and Vascular Surgery (T.M., A.N., C.J., P.G., G.M.) and Anesthesiology (Z.S.K.), Mayo Clinic and Foundation, Rochester, Minn.

Correspondence to Timothy O’Brien, MD, PhD, Mayo Clinic and Foundation, 200 First St SW, 5-194 Joseph, Rochester, MN 55905. E-mail obrien.timothy{at}mayo.edu

Background and Purpose—Hypercholesterolemia is associated with abnormal endothelium-dependent vasorelaxation due to decreased nitric oxide bioavailability. Our aim was to examine the effect of adenovirus-mediated gene transfer of endothelial nitric oxide synthase (eNOS) to the hypercholesterolemic rabbit carotid artery in vivo. In addition, we examined whether adenovirus-mediated gene transfer was associated with vascular dysfunction.

Methods—Rabbits were fed a 1% cholesterol diet for 4 weeks followed by a 0.5% cholesterol diet for 6 weeks. Vascular reactivity was assessed in nontransduced carotid arteries from chow- and cholesterol-fed animals. In addition, carotid arteries were surgically isolated, and 2 separate doses of adenoviral vectors encoding eNOS or ß-galactosidase (AdßGal) on the contralateral side were delivered to the lumen (1x10¹⁰ and 5x10¹⁰ pfu/mL).

Results—Abnormal acetylcholine-mediated endothelium-dependent vasorelaxation was detected in the carotid artery from cholesterol-fed animals, whereas responses to calcium ionophore A23187 and diethylamine NONOate were normal. Vascular reactivity was similar in nontransduced and AdßGal-transduced hypercholesterolemic vessels. In vessels transduced with eNOS, transgene expression was demonstrated by immunostaining in both the endothelium and the adventitia and by Western blot analysis. High-dose but not low-dose eNOS gene transfer enhanced endothelium-dependent relaxation in vessels from cholesterol-fed rabbits.

Conclusions—Adenovirus-mediated gene transfer of eNOS to carotid arteries of cholesterol-fed animals improves endothelium-dependent relaxation when an optimal viral titer is administered.

Editorial Comment

William G. Mayhan, PhD, Guest Editor

Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska

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