(Circulation. 1997;96:2254-2261.)
© 1997 American Heart Association, Inc.
Articles |
Adventitial Gene Transfer of Recombinant Endothelial Nitric Oxide Synthase to Rabbit Carotid Arteries Alters Vascular Reactivity
From the Divisions of Cardiovascular Disease (I.J.K., R.S.S.), Surgical Research (D.A.B.), Vascular Surgery (G.M., P.G.), Anatomic Pathology (T.B.C.), Anesthesiology and Pharmacology (Z.S.K.), and Endocrinology and Metabolism (T.O.), Mayo Clinic and Foundation, Rochester, Minn.
Correspondence to Timothy O'Brien, MD, Senior Associate Consultant, Department of Endocrinology and Metabolism, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail obrien.timothy{at}mayo.edu
Background Adventitial gene transfer may serve as a tool to study vascular biology and may have therapeutic potential. We investigated the hypothesis that adenovirus-mediated transfer of the gene for endothelial nitric oxide synthase (eNOS) to the adventitia would alter vascular reactivity.
Methods and Results Rabbit carotid arteries were surgically isolated and adenoviral vectors encoding eNOS (AdeNOS) or ß-galactosidase instilled into the periarterial sheath at a concentration of 1x1010 pfu/mL. Arteries were harvested 4 days later for immunostaining, NOS enzymatic assay, measurement of cGMP, and vasomotor studies. Transgene expression in the adventitia was confirmed by histochemistry for ß-galactosidase and immunostaining for eNOS with a monoclonal antibody. Calcium-dependent NOS enzymatic activity and cGMP levels were significantly greater in the AdeNOS-transduced arteries. Maximal contractions to phenylephrine (10-5 mol/L) were diminished in the AdeNOS-transduced arteries (4.6±0.2 versus 5.6±0.2 g; P<.05), but in the presence of the eNOS inhibitor NG-monomethyl-L-arginine (3x10-4 mol/L) there was no difference between the two groups (7.1±0.2 versus 7.5±0.3 g; P=NS). Relaxations to calcium ionophore obtained during submaximal contractions to phenylephrine were significantly enhanced in the AdeNOS-transduced arteries (-log EC50, 7.77±0.08 versus 7.45±0.07; P<.02).
Conclusions We conclude that eNOS gene transfer to the adventitia alters vascular reactivity, as demonstrated by diminished contractile responses to phenylephrine and enhanced relaxations to calcium ionophore. This may represent a therapeutic strategy for vascular diseases characterized by decreased bioavailability of NO.
Key Words: genes • nitric oxide • viruses
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