Zoledronate inhibits the proliferation, adhesion and migration of vascular smooth muscle cells

Bisphosphonates, which are extensively used in bone-related disorders, have been reported to inhibit atherosclerosis and neointimal hyperplasia. In the present study. we investigated the effects of a bisphosphonate, zoledronate, on the proliferation, adhesion, migration and microstructure of vascular smooth muscle cells (VSMCs) from Sprague-Dawley rats. It was shown that zoledronate suppressed VSMCs proliferation after 48 h cultivation in a dose depend manner, most obviously at concentrations above 10 mu M. Cell cycle analysis indicated that zoledronate inhibited the proliferation of VSMCs via cell cycle arrest at S/G2/M phase. This inhibition was not associated with cell death. In a modified Boyden chamber model, it was shown that zoledronate dose-dependently inhibited VSMCs adhesion to collagen and migration stimulated by platelet-derived growth factor-BB. Western blot analysis suggested that zoledronate significantly inhibited the phosphorylation of focal adhesion kinase. Furthermore, we observed that more and more VSMCs changed from a bipolar appearance to a globular shape under inverted light microscope as zoledronate concentration increased from 0.1 to 100 mu M. Images under transmission electron microscope confirmed this morphological change, and many electron density bodies were observed in zoledronate-treated VSMCs. These findings indicated that bisphosphonates' effects of suppressing atherosclerosis and neointimal hyperplasia might be due to inhibition of VSMCs, at least for zoledronate. (C) 2008 Elsevier B.V. All rights reserved.