Angiotensin II regulates the cell cycle of vascular smooth muscle cells from SHR

We have demonstrated that spontaneously hypertensive rats (SHR)-derived vas cular smooth muscle cells (VSMC) show the exaggerated growth and produce an giotensin II (Ang II). In the current study, we investigated the role of en dogenous Ang II in the regulation of the cell cycle in VSMC from SHR. Level s of Ang II in conditioned medium from SHR-derived VSMC cultured without se rum were significantly higher than levels in conditioned medium from Wistar -Kyoto (WKY) rat-derived VSMC. Basal DNA synthesis was higher in quiescent VSMC from SHR than that in cells from WKY rats. An Ang II type 1 receptor a ntagonist, CV11974, significantly inhibited the elevation in DNA synthesis in quiescent VSMC from SHR but did not affect it in cells from WKY rats. Ce llular DNA content analysis by flow cytometry revealed that the proportion of cells in S phase was higher, whereas the proportion of cells in G(1)+G(0 ) phase was lower in VSMC from SHR than those in cells from WKY rats. CV119 74 significantly decreased the proportion of cells in S phase and correspon dingly increased the proportion of cells in G(1)+G(0) phase in VSMC from SH R, but it did not affect the proportion in cells from WKY rats. Cyclin-depe ndent kinase 2 (CDK2) activity, which is known to induce the progression fr om G(1) to S phase, was higher in VSMC from SHR than in cells from WKY rats . Expression of CDK2 inhibitor p27(kip1) mRNA was markedly higher in VSMC f rom SHR than in cells from WKY rats. CV11974 decreased expression of p27(ki p1) mRNA in VSMC from SHR, whereas CV11974 increased it in cells from WKY r ats. These findings indicate that enhanced production of endogenous Ang II regulates the cell cycle especially in the progression from G(1) to S phase , and increases CDK2 activity, which is independent of p27(kip1) in VSMC fr om SHR. Am J Hypertens 2000; 13:1117-1124 (C) 2000 American Journal of Hype rtension, Ltd.