Expression of Q227L-G alpha(s) inhibits intimal vessel wall hyperplasia after balloon injury

Interaction between signaling pathways regulates many cellular functions, i ncluding proliferation. The G alpha (s)/cAMP pathway is known to inhibit si gnal flow from receptor tyrosine kinases to mitogen-activated protein kinas e (MAPK)-1,2 and, thus, inhibit proliferation. Elevation of cAMP or adenovi rus-directed expression of mutant (Q227L)-G alpha (s) (alpha (s)*) inhibits the proliferation of rat vascular smooth muscle cells (VSMCs) in culture. Platelet-derived growth factor (PDGF) stimulated MAPK activation and DNA sy nthesis was also blocked by expression of alpha (s)*. However, it is not kn own whether such mechanisms are operative in vivo. Proliferation of vascula r smooth muscle cells in vivo was induced by balloon injury of carotid arte ries in the rat. Recombinant adenovirus encoding beta -galactosidase (beta -gal) or alpha (s)* was applied to arterial segments injured by the balloon catheters. The alpha (s)*-treated vessels showed decreased phospho-MAPK st aining in the intima as compared with beta -gal-treated vessels. Applicatio n of alpha (s)*, but not beta -gal containing adenovirus, inhibited formati on of neointima by 50%. No change was observed in total vessel diameter or in the media or adventitia. These results suggest that the interaction betw een the G alpha (s) and MAPK pathways can regulate proliferation in vivo an d that targeted expression of activated G alpha (s) may have therapeutic po tential for the treatment of vascular pathophysiologies that arise from int imal hyperplasia.