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

The possibility that the antiproliferative effect of cyclic GMP‐ and cyclic 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 transition between the distinct phases of the cell cycle, was examined. FCS (10%) stimulated the transition of quiescent VSMC from the G0/G1 to the S phase (maximum within 18–24 h and then to the G2/M phase (maximum within 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 phase after FCS stimulation. FCS stimulated the low basal protein expression of cyclin D1 (maximum within 8–24 h) and E (maximum within 8–38 h) and of cyclin A (maximum within 14–30 h). The stimulatory effect of FCS on cyclin D1 and A expression was inhibited, but that of cyclin E was only minimally affected by the vasodilators. 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. These findings indicate that cyclic GMP‐ and cyclic AMP‐dependent vasodilators inhibit the proliferation of VSMC by preventing the progression of the cell cycle from the G0/G1 into the S phase, an effect which can be attributed to the impaired expression of cyclin D1 and A.British Journal of Pharmacology (1999) 126 , 349–357; doi: 10.1038/sj.bjp.0702305