Soluble guanylate cyclase alpha(1) and beta(1) gene transfer increases NO responsiveness and reduces neointima formation after balloon injury in ratsvia antiproliferative and antimigratory effects

In vascular smooth muscle cells, NO stimulates the synthesis of cGMP by sol uble guanylate cyclase (sGC), a heterodimer composed of alpha (1) and beta (1) subunits, NO/cGMP signal transduction affects multiple cell functions t hat contribute to neointima formation after Vascular injury. Balloon-induce d vascular injury was found to decrease sGC subunit expression and enzyme a ctivity in rat carotid arteries. The effect of restoring sGC enzyme activit y on neointima formation was investigated using recombinant adenoviruses sp ecifying sGC alpha (1) and beta (1) subunits (Ad alpha1 and Ad beta1). Coin fection of cultured rat aortic smooth muscle cells with Ad alpha1 and Ad be ta1 increased NO-stimulated intracellular cGMP levels 60-fold and decreased DNA synthesis and migration by 16% and 48%, respectively. Immunoreactivity for alpha (1) and beta (1) subunits colocalized in carotid arteries infect ed with Ad alpha1 and Ad beta1. Molsidomine-stimulated carotid tissue cGMP levels were greater after coinfection with Ad alpha1 and Ad beta1 than afte r infection with a control virus, AdRR5 (0.53 +/- 0.09 pmol/mg protein, mea n+/-SEM, versus 0.23+/-0.09, P<0.05). Mean intima/media ratio, 2 weeks afte r balloon injury and twice-daily administration of 5 mg/kg molsidomine, was less in rats coinfected with Ad<alpha>1 and Ad beta1 than in rats infected with AdRR5 or in uninfected rats (0.36+/-0.11 versus 0.81+/-0.13 and 0.75/-0.25, respectively, P<0.05). Thus, Ad<alpha>1 and Ad beta1 gene transfer to balloon-injured rat carotid arteries increases NO responsiveness and att enuates neointima formation via a direct antiproliferative and antimigrator y effect on vascular smooth muscle cells.