Growth-inhibitory effect of cyclic GMP and cyclic AMP dependent vasodilators on rat vascular smooth muscle cells: effect on cell cycle and cyclin expression

1 The possibility that the antiproliferative effect of cyclic GMP- and cycl ic AMP-dependent vasodilators involves an impaired progression of vascular smooth muscle cells (VSMC) through the cell cycle and expression of cyclins , which in association with the cyclin-dependent kinases control the transi tion between the distinct phases of the cell cycle, was examined. 2 FCS (10%) stimulated the transition of quiescent VSMC from the G0/G1 to t he S phase (maximum within 18-24 h and then to the G2/M phase (maximum with in 22-28 h). Sodium nitroprusside and 8-Br-cyclic GMP, as well as forskolin and 8-Br-cyclic AMP markedly reduced the percentage of cells in the S phas e after FCS stimulation. 3 FCS stimulated the low basal protein expression of cyclin D1 (maximum wit hin 8-24 h) and E (maximum within 8-38 h) and of cyclin A (maximum within 1 4-30 h). The stimulatory effect of FCS on cyclin D1 and A expression was in hibited, but that of cyclin E was only minimally affected by the vasodilato rs. 4 FCS increased the low basal level of cyclin D1 mRNA after a lag phase of 2 h and that of cyclin A after 12 h. The vasodilators significantly reduced the FCS-stimulated expression of cyclin D1 and A mRNA. 5 These findings indicate that cyclic GMP- and cyclic AMP-dependent vasodil ators inhibit the proliferation of VSMC by preventing the progression of th e cell cycle from the G0/G1 into the S phase, an effect which can be attrib uted to the impaired expression of cyclin D1 and A.