title: Adenosine diphosphate receptor P2Y12-mediated migration of host smooth muscle-like cells and leukocytes in the development of transplant arteriosclerosis.
abstract: BACKGROUND
  We have recently reported that platelet P2Y12 receptors may play a role in the development of transplant arteriosclerosis (TA). In the present study, we investigated the role of P2Y12 receptors on host-derived smooth muscle-like cells (SMLCs, including bone-marrow-derived SMLCs) and CD45+ leukocytes, both of which are believed to be associated with the development of TA, using P2Y12-deficient (KO) mice.
  
  
  METHODS
  Orthotopic carotid artery transplantation was performed from C3H/He (H-2k) donors into KO or wild-type (WT) recipient mice (129S:C57BL/6, H-2b). Grafts were harvested at 8 weeks after transplantation for histology. Plasma monocyte chemoattractant protein-1 (MCP-1) levels were analyzed with a kit. Cell migration was examined using a Boyden chamber system. The expression of MCP-1 messenger RNA was assessed by real-time polymerase chain reaction.
  
  
  RESULTS
  Eight weeks after allotransplantation, KO recipient mice showed a significant reduction of luminal occlusion, host-derived SMLCs, CD45+ leukocytes, MCP-1+ cells in the grafts, and of plasma MCP-1 levels. In addition, the migration of host-derived SMLCs (including bone-marrow-derived SMLCs) and CD45+ leukocytes stimulated with adenosine diphosphate (ADP) or 2-methylthio-ADP (2MeSADP, a stable ADP analog) was significantly decreased in KO mice. There were no significant changes in MCP-1-induced cell migration between WT and KO mice. The low concentration of 2MeSADP plus MCP-1 significantly increased cell migration in WT but not KO mice. Furthermore, 2MeSADP-induced MCP-1 messenger RNA expression was significantly reduced in the cells of KO mice.
  
  
  CONCLUSIONS
  Thus, the P2Y12-mediated migration of host-derived SMLCs and CD45+ leukocytes may play an important role in the development of TA, partly by MCP-1 pathways.
authors.affiliation: Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu City, Shizuoka, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Harada
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umemura
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology / Q000503:physiopathology*; D001853:Bone Marrow / Q000473:pathology; D002339:Carotid Arteries / Q000473:pathology / Q000503:physiopathology / Q000637:transplantation*; D002465:Cell Movement / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D058925:Receptors, Purinergic P2Y12 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C548577:P2ry12 protein, mouse; D058925:Receptors, Purinergic P2Y12; D013873:Thionucleotides; C002480:methylthio-ADP; D000244:Adenosine Diphosphate; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse