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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1604.)
© 2001 American Heart Association, Inc.

Vascular Biology

L-Arginine Administration Reduces Neointima Formation After Stent Injury in Rats by a Nitric Oxide-Mediated Mechanism

P. Vermeersch; Z. Nong; E. Stabile; O. Varenne; H. Gillijns; M. Pellens; N. Van Pelt; M. Hoylaerts; I. De Scheerder; D. Collen; S. Janssens

From the Center for Transgene Technology and Gene Therapy (P.V., Z.N., E.S., O.V., H.G., M.P., M.H., D.C.), Flanders Interuniversity Institute for Biotechnology, and the Department of Cardiology (N.V.P., I.D.S., S.J.), University of Leuven, Leuven, Belgium.

Correspondence to Stefan Janssens, MD, PhD, Center for Transgene Technology and Gene Therapy, 49 Herestraat, B-3000 Leuven, Belgium. E-mail stefan.janssens{at}med.kuleuven.ac.be

Abstract—— The clinical outcome of vascular stenting is limited by in-stent stenosis. Increased nitric oxide (NO)/cGMP signaling by L-arginine (L-Arg) supplementation, the substrate for NO synthase (NOS), or NOS gene transfer may reduce in-stent neointima formation. After stenting, vascular cell proliferation in rat carotid arteries, as measured by 5'-bromodeoxyuridine (5'-BrdU) incorporation, indicated 15±8%, 28±5%, and 33±7% 5'-BrdU-positive vascular cells at 4, 7, and 14 days, respectively. Reporter ß-galactosidase gene transfer efficacy was evidenced by 30% ß-galactosidase-expressing medial smooth muscle cells at 14 days. The intima-to-media ratio (I/M) progressively increased to 2.32±0.24 at 14 days. To target in-stent neointima formation, animals were infected with adenoviral vectors (4x10¹⁰ plaque-forming units per mL) expressing NOS2 (AdNOS2) or no transgene (AdRR5), or they received daily doses of L-Arg (500 mg · kg^-1 · ^d-1 IP). The neointima at 14 days was smaller in L-Arg-treated than in untreated rats (I/M 1.25±0.35 vs 2.32±0.24, P<0.05, n=7 each) or in AdRR5- and AdNOS2-infected rats (I/M 2.57±0.43, n=7 and 1.82±0.75, n=8, respectively; P<0.05 for both). The effect of L-Arg was abolished by simultaneous administration of N^G-nitro L-arginine methyl ester, an NOS inhibitor (2.03±0.39, P<0.05, vs L-Arg). Inflammation was markedly less in L-Arg- and AdNOS2-treated than in AdRR5-infected rats. Supplemental L-Arg reduces neointima formation after stenting by way of an NOS-dependent mechanism and may be a valuable strategy to target in-stent stenosis.

Key Words: arginine • neointima formation • gene therapy • stents • nitric oxide synthase