Cell-type- and cell-cycle-specific anti-mitogenesis by cicaprost

Stents eluting anti-proliferative drugs limit restenosis, but drugs commonly used to date are relatively non-specific cytostatic agents which inhibit proliferation of intimal endothelial cells as well as medial smooth muscle cells and may thereby contribute to the clinical complications associated with angioplasty. In an effort to identify a more specific anti-proliferative agent, we compared the effects of rapamycin to those of cicaprost, a mimetic of the naturally occurring anti-mitogen, PGI2. Rapamycin and cicaprost were both strongly anti-mitogenic in vascular smooth muscle cells (VSMCs). But unlike rapamycin, cicaprost did not inhibit mitogenesis in aortic endothelial cells even when used at concentrations >10-fold higher than its ED50 for VSMCs. Similarly, both rapamycin and cicaprost have been reported to regulate levels of the cdk inhibitor, p27kip1. But rapamycin remained anti-mitogenic in p27kip1-null VSMCs whereas the anti-mitogenic effect of cicaprost was completely dependent on p27kip1. We conclude that stable PGI2 mimetics may be highly specific inhibitors of p27kip1-dependent VSMC proliferation after vascular injury.