The role of hyaluronan and its receptors in restenosis after balloon angioplasty: Development of a potential therapy

Atherosclerosis is a progressive condition that is initiated by endothelial injury, promoted by growth factors, and which results in the formation of fibrofatty plaques that narrow the affected blood vessel. Balloon angioplasty is used to dilate these plaques in the coronary circulation so as to prevent occlusion of this critical blood supply. However, 30-50% of balloon dilatations end in restenosis within six months of the procedure. The pathogenesis of both atherosclerosis and restenosis after balloon angioplasty involves the migration of medial smooth-muscle cells across the internal elastic lamina to form a neointima. Proliferation of these cells and their elaboration of an extracellular matrix results in stenosis of the affected area. Investigation of several animal models, as well as of the human condition, indicates the presence of an ongoing inflammatory reaction involving T cells and other leukocytes which probably maintain smooth-muscle cell migration, proliferation and matrix deposition. We have shown that the stenotic response involves the expression of HA (hyaluronan) receptors on both the infiltrating white cells and on smooth-muscle cell populations. Thus, in vitro, the locomotion and chemotaxis of these cells in response to injury is inhibited by reagents that block HA-receptor interactions including HA-binding peptides and high doses of HA. Further, the expression of these HA receptors is up-regulated after balloon-catheter injury of the rat carotid artery, and exposure of injured arteries to high concentrations of HA in vivo results in significant inhibition of neointimal formation. The possible clinical benefits of this response are discussed.