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(Hypertension. 1997;30:314.)
© 1997 American Heart Association, Inc.

Articles

Enhanced Endothelium-Dependent Relaxations After Gene Transfer of Recombinant Endothelial Nitric Oxide Synthase to Rabbit Carotid Arteries

Iftikhar J. Kullo¹; Geza Mozes¹; Robert S. Schwartz; Peter Gloviczki; Masato Tsutsui; Zvonimir S. Katusic; Timothy O’Brien

From the Divisions of Cardiovascular Disease (I.J.K., R.S.S.), Vascular Surgery (G.M., P.G.), Anesthesiology and Pharmacology (M.T., Z.S.K.), and Endocrinology and Metabolism (T.O.), Mayo Clinic and Foundation, Rochester, Minn.

Correspondence to Timothy O’Brien, MD, Assistant Professor, Department of Endocrinology and Metabolism, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail OBrien.Timothy{at}mayo.edu

Abstract We tested the effects of overexpression of the endothelial nitric oxide synthase (eNOS) gene in the normal arterial wall by adenoviral-mediated gene transfer. Rabbit carotid arteries were surgically isolated and exposed to adenoviral vectors encoding eNOS (AdeNOS) or ß-galactosidase (AdßGal) on the contralateral side. Vector solutions at a concentration of 1x10¹⁰ plaque forming units/mL were instilled for 20 minutes before restoration of flow. Arteries were harvested 4 days later for immunostaining, measurement of cGMP, and vasomotor studies. Endothelium-specific gene transfer was confirmed by staining for ß-galactosidase in the AdßGal arteries. Immunostaining of en face endothelial cell imprints from AdeNOS-transduced arteries with a monoclonal antibody to eNOS showed increased immunoreactivity. Basal cGMP levels were significantly greater in the AdeNOS-transduced arteries (18.4±4.6 versus 4.2±0.5 pmol/mg protein; P<.05). Contractions to phenylephrine were significantly reduced in the AdeNOS-transduced arteries (area under curve, 106±5 versus 119±7; P<.05), but in the presence of the eNOS inhibitor, N^G-monomethyl-L-arginine (L-NMMA, 3x10^-4 mol/L), there was no difference between the two (area under curve, 148±5 versus 153±6; P=NS). Relaxations to acetylcholine obtained during submaximal contractions to phenylephrine were significantly enhanced in the AdeNOS-transduced arteries (EC₅₀, 7.45±0.05 versus 7.23±0.03; P<.05). We conclude that overexpression of eNOS in the endothelium results in diminished contractile responses, as well as enhanced endothelium-dependent relaxations. These findings imply a possible role for vascular eNOS gene transfer in the treatment of vasospasm and endothelial dysfunction.

Key Words: nitric oxide • gene transfer • endothelium • nitric oxide synthase • adenovirus

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