title: The perlecan fragment LG3 is a novel regulator of obliterative remodeling associated with allograft vascular rejection.
abstract: BACKGROUND
  Endothelial apoptosis is increased in association with acute and chronic vascular rejection (VR) of solid allografts. Apoptotic endothelial cells (EC) release LG3, a C-terminal fragment of perlecan of potential importance in vascular remodeling and neointima formation.
  
  
  OBJECTIVE
  Our 2 goals were to determine whether circulating levels of LG3 are increased in association with acute VR of renal allografts and to evaluate the impact of LG3 on vascular remodeling.
  
  
  RESULTS
  We conducted a case-control study to compare serum LG3 levels in human renal transplant patients with acute VR, tubulo-interstitial rejection (ATIR) and normal graft function. Aorta transplantation between fully MHC-mismatched mice in association with intravenous LG3 injection was used to characterize the impact of LG3 on vascular remodeling. Scratch assays evaluated the promigratory activity of LG3 on vascular smooth muscle cells (VSMC) in vitro. Serum LG3 levels were significantly elevated in human renal transplant patients with acute VR (n = 16) compared to ATIR (n = 16) and normal graft function (n = 32, P = 0.004). In patients with acute VR, graft loss was associated with elevated LG3 levels. Increasing LG3 serum levels in aortic allograft recipients significantly increased neointima formation. LG3 injection fostered accumulation of α-smooth muscle actin-positive cells and decreased the number of CD31 positive EC. LG3 increased the migration of VSMC through extracellular signal-regulated kinases 1/2-dependent pathways.
  
  
  CONCLUSIONS
  These results indicate that LG3 is a novel regulator of obliterative vascular remodeling during rejection.
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal, Hôpital Notre Dame and Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Soulez
authors.forename: Eve-Annie
authors.initials: EA
authors.lastname: Pilon
authors.forename: Mélanie
authors.initials: M
authors.lastname: Dieudé
authors.forename: Héloïse
authors.initials: H
authors.lastname: Cardinal
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brassard
authors.forename: Shijie
authors.initials: S
authors.lastname: Qi
authors.forename: Shyh-Jong
authors.initials: SJ
authors.lastname: Wu
authors.forename: Yves
authors.initials: Y
authors.lastname: Durocher
authors.forename: François
authors.initials: F
authors.lastname: Madore
authors.forename: Claude
authors.initials: C
authors.lastname: Perreault
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Hébert
mesh_terms: D000328:Adult; D000818:Animals; D001011:Aorta / Q000637:transplantation; D017209:Apoptosis / Q000502:physiology; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006084:Graft Rejection / Q000503:physiopathology*; D019812:Heparan Sulfate Proteoglycans / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D016030:Kidney Transplantation / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D058426:Neointima / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D011379:Prognosis; D051381:Rats; D012189:Retrospective Studies; D014184:Transplantation, Homologous
chemical_list: D019812:Heparan Sulfate Proteoglycans; D010446:Peptide Fragments; C071927:perlecan