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Growth-inhibitory effect of cyclic GMP- and cyclic AMP-dependent vasodilators on rat vascular smooth muscle cells:
N Kronemann1, W A Nockher, R Busse
1Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany.
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.
Insights
Cyclic GMP- and cyclic AMP-dependent vasodilators inhibit vascular smooth muscle cell proliferation by blocking cell cycle progression. This effect is linked to reduced expression of key cell cycle proteins, cyclin D1 and cyclin A.
Area of Science:
- Vascular Biology
- Cell Cycle Regulation
- Pharmacology
Background:
- Vascular smooth muscle cell (VSMC) proliferation is crucial for vascular health.
- Cyclic nucleotides (cGMP and cAMP) are known regulators of VSMC function.
- The precise mechanisms by which vasodilators influence VSMC cell cycle progression are not fully understood.
Purpose of the Study:
- To investigate the antiproliferative effects of cGMP- and cAMP-dependent vasodilators on VSMCs.
- To determine if these vasodilators impair VSMC cell cycle progression and cyclin expression.
- To elucidate the role of cyclins D1, E, and A in mediating these effects.
Main Methods:
- VSMCs were stimulated with fetal calf serum (FCS) to induce cell cycle progression.
- Cells were treated with vasodilators (sodium nitroprusside, 8-Br-cGMP, forskolin, 8-Br-cAMP).
- Cell cycle phase distribution, cyclin protein, and mRNA expression were analyzed using flow cytometry and molecular techniques.
Main Results:
- FCS stimulated VSMC transition from G0/G1 to S and G2/M phases.
- Vasodilators significantly reduced the percentage of cells in the S phase.
- FCS-induced expression of cyclin D1 and A proteins and mRNA was inhibited by vasodilators, while cyclin E was minimally affected.
Conclusions:
- cGMP- and cAMP-dependent vasodilators inhibit VSMC proliferation.
- This inhibition occurs by preventing cell cycle progression from G0/G1 to S phase.
- Impaired expression of cyclin D1 and A mediates the antiproliferative effect of these vasodilators.