Hyaluronan enhances contraction of collagen by smooth muscle cells and adventitial fibroblasts - Role of CD44 and implications for constrictive remodeling

Remodeling contributes to restenosis when cells shrink the artery wall at sites of injury. This may be analogous to wound healing, where tissue remodeling achieves wound contraction. Hyaluronan (HA) is prominent in wound matrix and inhibits fetal scarring. HA is also produced in the artery wall after angioplasty, where it may inhibit constrictive remodeling. This hypothesis was tested in vitro using a model of matrix contraction. Primate aortic smooth muscle cells and adventitial fibroblasts were seeded into collagen I gels containing increasing amounts of HA (0% to 50%, wt/wt). Both cell types reduced the diameter of collagen alone approximate to 65% at 18 hours. HA significantly increased gel contraction (diameter in mm: 0% HA, 7.7+/-0.9; 2%, 7.1+/-0.7; 10%, 6.7+/-0.5; 50%, 5.6+/-0.9; P<0.05 for <greater than or equal to>10%), cell spreading and telopodia, and pericellular accumulation of collagen fibrils. These effects were mediated in part by cellular HA binding, because an antibody against CD44 receptors blocked pericellular collagen accumulation and enhanced gel contraction without altering cell shape. The role of CD44 was specific, because inhibiting receptor for hyaluronic acid-mediated motility (RHAMM) had no effect. Blocking beta (1)-integrins completely inhibited contraction of collagen, but gels containing HA required CD44 and beta (1)-integrin blockade for complete inhibition. Enhanced collagen reorganization and contraction were not attributable to increased collagenase activity, because the metalloproteinase inhibitor batimastat had no effect. In summary, HA enhanced collagen reorganization by the cell types most likely to mediate constrictive remodeling after angioplasty. These effects were CD44-dependent, thus providing a potential target for therapies to prevent constrictive remodeling and restenosis.