© 1998 American Heart Association, Inc.
Original Contributions |
Improvement of Relaxation in an Atherosclerotic Artery by Gene Transfer of Endothelial Nitric Oxide Synthase
From the Departments of Internal Medicine and Pharmacology (F.M.F., D.D.H.), Cardiovascular Center and Center on Aging, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City.
Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail donald-heistad{at}uiowa.edu
Abstract—Gene transfer
with replication-deficient adenovirus is a useful tool to study
vascular biology. We have reported that overexpression of
endothelial nitric oxide (NO) in carotid arteries from
normal rabbits augments vasorelaxation mediated by NO. In this study,
we tested the hypothesis that adenovirus-mediated gene transfer of
endothelial nitric oxide synthase (eNOS) improves
impaired relaxation of atherosclerotic vessels. We used 2
replication-deficient adenoviruses: AdeNOS, which carries cDNA for
eNOS, and Adßgal, which expresses ß-galactosidase. Common carotid
arteries from 10 New Zealand White (NZW; plasma
cholesterol, 79±13 mg/dL) and 10 Watanabe heritable
hyperlipidemic (WHHL; plasma cholesterol,
452±39 mg/dL) rabbits were incubated in organ culture with AdeNOS,
Adßgal, or vehicle alone. Carotid arteries from WHHL rabbits had mild
to moderate atherosclerotic lesions. Histochemical staining for
ß-galactosidase and immunohistochemistry for eNOS indicated transgene
expression in the endothelium and adventitia in both
NZW and WHHL rabbits. Expression of eNOS determined with Western blot
analysis after incubation with AdeNOS tended to be higher in
vessels from WHHL rabbits than NZW rabbits. Effects of transgene
expression on vascular function were examined by recording
isometric tension 1 day after transduction. After precontraction with
phenylephrine, acetylcholine produced significantly less
relaxation in vessels from WHHL rabbits than in vessels from NZW
rabbits. Relaxation in response to acetylcholine was greater in carotid
arteries from both NZW and WHHL rabbits that were transfected with
AdeNOS than in vessels treated with vehicle or Adßgal. Vasorelaxation
in response to acetylcholine was inhibited by
N
-nitro-L-arginine. Responses
to sodium nitroprusside were similar after treatment with vehicle
alone, Adßgal, or AdeNOS in both groups of rabbits. Thus,
overexpression of eNOS with an adenoviral vector improves impaired
NO-mediated relaxation in atherosclerotic arteries.
Key Words: adenovirus • atherosclerosis • gene transfer • nitric oxide synthase • vasorelaxation
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