Formation of hyaluronan- and versican-rich pericellular matrix is requiredfor proliferation and migration of vascular smooth muscle cells

The accumulation of hyaluronan (HA) and the HA-binding proteoglycan versica n around smooth muscle cells in lesions of atherosclerosis suggests that to gether these molecules play an important role in the events of atherogenesi s. In this study we have examined the formation of HA- and versican-rich pe ricellular matrices by human aortic smooth muscle cells in vitro, using a p article-exclusion assay, and the role of the pericellular matrix in cell pr oliferation and migration. The structural dependence of the pericellular ma trix on HA can be demonstrated by the complete removal of the matrix with S treptomyces hyaluronidase. The presence of versican in the pericellular mat rix was confirmed immunocytochemically. By electron microscopy, the cell co at was seen as a tangled network of hyaluronidase-sensitive filaments decor ated with ruthenium red-positive proteoglycan granules. Ninety percent of m igrating cells in wounded cultures, and virtually all mitotic cells, displa yed abundant HA- and versican-rich coats. Time-lapse video imaging revealed that HA- and versican-rich pericellular matrix formation is dynamic and ra pid, and coordinated specifically with cell detachment and mitotic cell rou nding. HA oligosaccharides, which inhibit the binding of HA to the cell sur face and prevent pericellular matrix formation, significantly reduced proli feration and migration in response to platelet-derived growth factor, where as larger HA fragments and high molecular weight HA had no effect. Treatmen t with HA oligosaccharides also led to changes in cell shape from a typical fusiform morphology to a more spread and flattened appearance. These data suggest that organization of HA- and versican-rich pericellular matrices ma y facilitate migration and mitosis by diminishing cell surface adhesivity a nd affecting cell shape through steric exclusion and the viscous properties of HA proteoglycan gels.