title: Loss of the hyaluronan receptor RHAMM prevents constrictive artery wall remodeling.
abstract: OBJECTIVE
  Constrictive extracellular matrix (ECM) remodeling contributes significantly to restenosis after arterial reconstruction, but its molecular regulation is poorly defined. Hyaluronan (HA) accumulates within ECM at sites of injury where it is thought to facilitate smooth muscle cell (SMC) trafficking and collagen remodeling analogous to its role in cutaneous wound healing. SMC receptors for HA include receptor for hyaluronan-mediated motility (RHAMM), which mediates HA-induced migration. We hypothesized RHAMM would also mediate SMC-matrix interactions to alter the extent of constrictive remodeling.
  
  
  METHODS
  We studied the role of RHAMM in SMC attachment to collagen, migration, and contraction of collagen gels using blocking antibodies and SMC from RHAMM -/- knockout mice. We then determined the role of RHAMM in constrictive artery wall remodeling by comparing changes in wall geometry in RHAMM -/- vs wild-type (WT) RHAMM +/+ controls 1 month after carotid ligation.
  
  
  RESULTS
  HA increased SMC attachment to collagen-coated plates, but blocking RHAMM reduced adhesion (P = .025). RHAMM -/- SMC also demonstrated reduced adhesion (% adherent: 36.1 ± 2.2 vs 76.3 ± 1.9; P < .05). SMC contraction of collagen gels was enhanced by HA and further increased by RHAMM blockade (P < .01) or knockout (gel diameter, mm: RHAMM -/-, 6.7 ± 0.1 vs WT 9.8 ± 0.1; P < .01). RHAMM promoted constrictive remodeling in vivo as carotid artery size was significantly larger in knockout mice 1 month after ligation. Neointimal thickening, however, was not affected in RHAMM -/- (P = NS vs WT), but lumen size was significantly larger (lumen area, μm(2): 52.4 ± 1.4 × 10(3) vs 10.4 ± 1.8 × 10(3); P = .01) because artery size constricted less (external elastic lamina area, μm(2): RHAMM -/-, 92.4 ± 4.7 × 10(3) vs WT, 51.3 ± 5.9 × 10(3); P = .015). Adventitial thickening and collagen deposition were also more extensive in ligated RHAMM -/- carotids (adventitial thickness, μm: 218 ± 12.2 vs 109 ± 7.9; P = .01).
  
  
  CONCLUSIONS
  HA activation of RHAMM significantly impacts SMC-ECM adhesive interactions and contributes to constrictive artery wall remodeling in mice. Strategies to block RHAMM at sites of vessel injury may prove useful in the prevention of clinical restenosis.
authors.affiliation: Department of Vascular and Endovascular Surgery, Wake Forest University Health Sciences, Winston-Salem, NC.
authors.forename: Xue
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Vascular and Endovascular Surgery, Wake Forest University Health Sciences, Winston-Salem, NC.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Pearce
authors.affiliation: Department of Vascular and Endovascular Surgery, Wake Forest University Health Sciences, Winston-Salem, NC.
authors.forename: David B
authors.initials: DB
authors.lastname: Wilson
authors.affiliation: Department of Vascular and Endovascular Surgery, Wake Forest University Health Sciences, Winston-Salem, NC.
authors.forename: William P
authors.initials: WP
authors.lastname: English
authors.affiliation: Department of Vascular and Endovascular Surgery, Wake Forest University Health Sciences, Winston-Salem, NC.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Edwards
authors.affiliation: Department of Vascular and Endovascular Surgery, Wake Forest University Health Sciences, Winston-Salem, NC. Electronic address: rgeary@wakehealth.edu.
authors.forename: Randolph L
authors.initials: RL
authors.lastname: Geary
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D016893:Carotid Stenosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D048430:Cell Shape; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor; D006820:Hyaluronic Acid