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 endoth elial injury, promoted by growth factors, and which results in the for mation of fibrofatty plaques that narrow the affected blood vessel. Ba lloon angioplasty is used to dilate these plaques in the coronary circ ulation so as to prevent occlusion of this critical blood supply. Howe ver, 30-50% of balloon dilatations end in restenosis within six months of the procedure. The pathogenesis of both atherosclerosis and resten osis after balloon angioplasty involves the migration of medial smooth -muscle cells across the internal elastic lamina to form a neointima. Proliferation oi these cells and their elaboration of an extracellular matrix results in stenosis of the affected area. investigation of sev eral animal models, as well as of the hu,nan condition, indicates the presence of an ongoing inflammatory reaction involving T cells and oth er leukocytes which probably maintain smooth-muscle cell migration, pr oliferation and matrix deposition. We have shown that the stenotic res ponse 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 in cluding HA-binding peptides and high doses of HA. Further, the express ion oi these HA receptors is up-regulated after balloon-catheter injur y of the rat carotid artery, and exposure of injured arteries to high concentrations of HA in vivo results in significant inhibition of neoi ntimal formation. The possible ciinical benefits of this response are discussed.