title: Donor and recipient cell surface colony stimulating factor-1 promote neointimal formation in transplant-associated arteriosclerosis.
abstract: OBJECTIVE
  Transplant-associated arteriosclerosis manifests as progressive vascular neointimal expansion throughout the arterial system of allografted solid organs, and eventually compromises graft perfusion and function. Allografts placed in colony stimulating factor (CSF)-1-deficient osteopetrotic (Csf1(op)/Csf1(op)) mice develop very little neointima, a finding attributed to impaired recipient macrophage function. We examined how CSF-1 affects neointima-derived vascular smooth muscle cells, tested the significance of CSF-1 expressed in donor tissue, and evaluated the contribution of secreted versus cell surface CSF-1 isoforms in transplant-associated arteriosclerosis.
  
  
  RESULTS
  CSF-1 activated specific signaling pathways to promote migration, survival, and proliferation of cultured vascular smooth muscle cells. Tumor necrosis factor-α addition increased CSF-1 and CSF-1 receptor expression, and tumor necrosis factor-α-driven proliferation was blocked by anti-CSF-1 antibody. In a mouse vascular allograft model, lack of recipient or donor CSF-1 impaired neointima formation; the latter suggests local CSF-1 function within the allograft. Moreover, reconstitution of donor or recipient cell surface CSF-1, without secreted CSF-1, restored neointimal formation.
  
  
  CONCLUSIONS
  Vascular smooth muscle cells activation, including that mediated by tumor necrosis factor-α, can be driven in an autocrine/juxtacrine manner by CSF-1. These studies provide evidence for local function of CSF-1 in neointimal expansion, and identify CSF-1 signaling in vascular smooth muscle cells, particularly cell surface CSF-1 signaling, as a target for therapeutic strategies in transplant-associated arteriosclerosis.
authors.affiliation: Department of Medicine (Cardiovascular Division), Albert Einstein College of Medicine, Forchheimer G46, 1300 Morris Park Ave, Bronx, NY 10461, USA.
authors.forename: Shungo
authors.initials: S
authors.lastname: Hiroyasu
authors.forename: Prameladevi
authors.initials: P
authors.lastname: Chinnasamy
authors.forename: Rong
authors.initials: R
authors.lastname: Hou
authors.forename: Kylie
authors.initials: K
authors.lastname: Hotchkiss
authors.forename: Isabel
authors.initials: I
authors.lastname: Casimiro
authors.forename: Xu-Ming
authors.initials: XM
authors.lastname: Dai
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stanley
authors.forename: Nicholas E S
authors.initials: NE
authors.lastname: Sibinga
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D002340:Carotid Artery Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005838:Genotype; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D058539:Phosphatidylinositol 3-Kinase; D016186:Receptor, Macrophage Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases