L-arginine administration reduces neointima formation after stent injury in rats by a nitric oxide-mediated mechanism

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 β-galactosidase gene transfer efficacy was evidenced by 30% β-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 (4×1010 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 NG-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.