Cell division fidelity is altered during the vascular response to injury: its novel role in atherosclerosis progression.

The rapid proliferation of smooth muscle cells (SMCs) contributes to atherosclerotic plaque formation and neointimal thickening in other occlusive vascular diseases. In cancer cells, rapid cell proliferation is often accompanied by DNA damage, division aberrations, elevated cell apoptosis, or accumulation of abnormal cells. However, little is known about division fidelity in vascular disorders. We have analyzed the cell division fidelity during the rapid SMC proliferation that occurs after balloon injury of the rat carotid artery using en face confocal microscopy of the full thickness of the vessel wall. SMCs newly migrated to the neointima had increased division defects and increased apoptosis compared with SMCs in the subjacent media, despite comparable mitosis rates. Protein kinase Cα and the receptor for hyaluronic acid-mediated motility (RHAMM) regulate division fidelity in cultured neointimal SMCs. The centrosomal targeting sequence of RHAMM was required for localization to the mitotic spindle and spindle organization. Dynein and RHAMM colocalized in the spindle area and were part of a complex. Dynein inhibition caused spindle defects similar to RHAMM or protein kinase C inhibition. Our study uncovered abnormalities in rapidly proliferating SMCs after arterial injury that could contribute to the growth of atherosclerotic plaques and reduce plaque stability by triggering apoptosis, and it described a mechanism by which RHAMM and dynein coordinate division fidelity in neointimal SMCs.