Soluble Guanylate Cyclase a1 and b1 Gene Transfer Increases NO Responsiveness and Reduces Neointima Formation After Balloon Injury in Rats via Antiproliferative and Antimigratory Effects

Abstract—In vascular smooth muscle cells, NO stimulates the synthesis of cGMP by soluble guanylate cyclase (sGC), a heterodimer composed of a1 and b1 subunits. NO/cGMP signal transduction affects multiple cell functions that contribute to neointima formation after vascular injury. Balloon-induced vascular injury was found to decrease sGC subunit expression and enzyme activity in rat carotid arteries. The effect of restoring sGC enzyme activity on neointima formation was investigated using recombinant adenoviruses specifying sGC a1 and b1 subunits (Ada1 and Adb1). Coinfection of cultured rat aortic smooth muscle cells with Ada1 and Adb1 increased NO-stimulated intracellular cGMP levels 60-fold and decreased DNA synthesis and migration by 16 % and 48%, respectively. Immunoreactivity for a1 and b1 subunits colocalized in carotid arteries infected with Ada1 and Adb1. Molsidomine-stimulated carotid tissue cGMP levels were greater after coinfection with Ada1 and Adb1 than after infection with a control virus, AdRR5 (0.5360.09 pmol/mg protein, mean6SEM, versus 0.2360.09, P,0.05). Mean intima/media ratio, 2 weeks after balloon injury and twice-daily administration of 5 mg/kg molsidomine, was less in rats coinfected with Ada1 and Adb1 than in rats infected with AdRR5 or in uninfected rats (0.3660.11 versus 0.8160.13 and 0.7560.25, respectively, P,0.05). Thus, Ada1 and Adb1 gene transfer to balloon-injured rat carotid arteries increases NO responsiveness and attenuates neointima formation via a direct antiproliferative and antimigratory effect on vascular smooth muscle cells. (Circ Res. 2001;88:103-109.