© 2001 American Heart Association, Inc.
Cellular Biology |
Hyaluronan Enhances Contraction of Collagen by Smooth Muscle Cells and Adventitial Fibroblasts
Role of CD44 and Implications for Constrictive Remodeling
From the Departments of Surgery (J.A.T., M.G.H., J.M.W., R.L.G.) and Pathology, Section on Comparative Medicine (W.D.W., R.L.G.), Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to Randolph L. Geary, MD, FACS, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157. E-mail rgeary{at}wfubmc.edu
Abstract—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 
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 
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
ß1-integrins completely inhibited contraction
of collagen, but gels containing HA required CD44 and
ß1-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.
Key Words: hyaluronan • smooth muscle cells • adventitial fibroblasts • restenosis • remodeling
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