INHIBITION OF HUMAN VASCULAR SMOOTH-MUSCLE CELL-MIGRATION AND PROLIFERATION BY BETA-CYCLODEXTRIN TETRADECASULFATE

Smooth muscle cell migration and proliferation are important regulator y processes in the development of intimal thickening after vascular in jury. beta-cyclodextrin tetradecasulfate, an orally active synthetic h eparin mimic, is effective in inhibiting rabbit aortic smooth muscle c ell proliferation in vitro and in limiting restenosis in an experiment al angioplasty restenosis model in rabbits (Herrmann et al., 1993). Ho wever, its effects on migration are unknown, as are its effects on hum an vascular smooth muscle cell biology in general. Using a Transwell a ssay system, we demonstrated a dose dependent inhibition of human vasc ular smooth muscle cell random migration for beta-cyclodextrin tetrade casulfate with half maximal inhibition between 100-500 mu g/ml and 85 +/- 1% inhibition at 10(3) mu g/ml (P < .001, n = 4). At this latter c oncentration, inhibition of migration was also demonstrable using a li near under-agarose assay, where the mean velocity for beta-cyclodextri n tetradecasulfate-treated cells (8 +/- 2 mu m/h, +/- S.E) was signifi cantly less than for control cells (21 +/- 4, P < .01), but equaled th at of control cells 48 h after drug withdrawal (21 +/- 1, P = NS). Sin gle cell analysis over 17 h using time lapse video microscopy revealed significant inhibition of total migration pathway distance for beta-c yclodextrin tetradecasulfate-treated smooth muscle cells compared with control smooth muscle cells (0.40 +/- 0.03 mm vs. 0.73 +/- 0.03, P < .01). We also demonstrated a dose-dependent inhibition of serum-induce d proliferation by beta-cyclodextrin tetradecasulfate in both cultured human umbilical vein and coronary artery smooth muscle cells. To asse ss whether beta-cyclodextrin tetradecasulfate had any direct cellular toxicity, we measured the release of intracellular LDH at 6 or 24 h. A t 10(3) mu g/ml or less, there was no increase in LDH release compared with untreated cultures. Thus, beta-cyclodextrin tetradecasulfate may be an effective agent in inhibiting intimal thickening after vascular injury by limiting both smooth muscle cell migration and proliferatio n.