title: VEGFR-1 and -2 regulate inflammation, myocardial angiogenesis, and arteriosclerosis in chronically rejecting cardiac allografts.
abstract: OBJECTIVE
  Interplay between inflammation and angiogenesis is important in pathological reparative processes such as arteriosclerosis. We investigated how the two vascular endothelial growth factor receptors VEGFR-1 and -2 regulate these events in chronically rejecting cardiac allografts.
  
  
  RESULTS
  Chronic rejection in mouse cardiac allografts induced primitive myocardial, adventitial, and intimal angiogenesis with endothelial expression of CD31, stem cell marker c-kit, and VEGFR-2. Experiments using marker gene mice or rats as cardiac allograft recipients revealed that replacement of cardiac allograft endothelial cells with recipient bone marrow- or non-bone marrow-derived cells was rare and restricted only to sites with severe injury. Targeting VEGFR-1 with neutralizing antibodies in mice reduced allograft CD11b+ myelomonocyte infiltration and allograft arteriosclerosis. VEGFR-2 inhibition prevented myocardial c-kit+ and CD31+ angiogenesis in the allograft, and decreased allograft inflammation and arteriosclerosis.
  
  
  CONCLUSIONS
  These results suggest interplay of inflammation, primitive donor-derived myocardial angiogenesis, and arteriosclerosis in transplanted hearts, and that targeting VEGFR-1 and -2 differentially regulate these pathological reparative processes.
authors.affiliation: Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Finland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Raisky
authors.forename: Antti I
authors.initials: AI
authors.lastname: Nykänen
authors.forename: Rainer
authors.initials: R
authors.lastname: Krebs
authors.forename: Maria
authors.initials: M
authors.lastname: Hollmén
authors.forename: Mikko A I
authors.initials: MA
authors.lastname: Keränen
authors.forename: Jussi M
authors.initials: JM
authors.lastname: Tikkanen
authors.forename: Roope
authors.initials: R
authors.lastname: Sihvola
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: Petri
authors.initials: P
authors.lastname: Salven
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Petri K
authors.initials: PK
authors.lastname: Koskinen
authors.forename: Karl B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D002196:Capillaries / Q000378:metabolism; D002454:Cell Differentiation; D002908:Chronic Disease; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D042783:Endothelial Cells / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D006084:Graft Rejection / Q000150:complications* / Q000378:metabolism; D016027:Heart Transplantation; D051379:Mice; D008815:Mice, Inbred Strains; D009205:Myocarditis / Q000209:etiology*; D009206:Myocardium / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000209:etiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D014184:Transplantation, Homologous; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016207:Cytokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D019009:Proto-Oncogene Proteins c-kit; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2