Distinct role of cAMP and cGMP in the cell cycle control of vascular smooth muscle cells - cGMP delays cell cycle transition through suppression of cyclin D1 and cyclin-dependent kinase 4 activation

cAMP and cGMP are known to suppress vascular smooth muscle cell (SMC) proli feration. In this study, our aim was to delineate the molecular mechanism u nderlying cAMP and cGMP suppression of cell cycle transition in human SMCs, cAMP inhibits both platelet-derived growth factor-stimulated cyclin-depend ent kinase (cdk) 2 and cdk4 activation through upregulation of the cdk2 inh ibitor p27(Kip1) and downregulation of cyclin D1 expression, which leads to a complete arrest of the cells in phase G(1). In contrast, cGMP inhibits c yclin D1 expression, inhibits cdk4 activation, and delays platelet-derived growth factor-mediated cdk2 activation, resulting in a delay in G(1)/S tran sition. A transient increase in p27(Kip1) in cdk2 immunoprecipitates, witho ut changes in total cellular p27(Kip1) levels, correlates with the delay in cdk2 activation caused by cGMP, Thus, cAMP and cGMP differentially affect cell cycle through distinct regulation of cell cycle molecules in human SMC s.