January 1999, Volume 126, Issue 1, Pages 349 - 357

Original Article

Growth-inhibitory effect of cyclic GMP- and cyclic AMP-dependent vasodilators on rat vascular smooth muscle cells: effect on cell cycle and cyclin expression Nicola Kronemann1, Wolfgang A. Nockher2,4, Rudi Busse1 & Valérie B. Schini-Kerth1,3 1Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Sterm-Kai 7, D-60590 Frankfurt am Main, Germany     2Medizinische Klinik IV, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany     3Author for correspondence: E-mail: schini-kerth@em.uni-frankfurt.de 4Current address: Institut für Klinische Chemie, Klinikum Großhadern, Ludwig Maximilians-Universität, D-81366 München, Germany

Keywords

VSMC;   proliferation;   nitric oxide donor;   sodium nitroprusside;   forskolin;   8-Br-cyclic GMP;   8-Br-cyclic AMP;   cell cycle;   cyclins

Abstract

1   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. 2   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. 3   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. 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 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.

Received 3 September 1998; Revised 16 October 1998; Accepted 20 October 1998

^© Macmillan Publishers Ltd 1999