VEGFR-1 and -2 regulate inflammation, myocardial angiogenesis, and arteriosclerosis in chronically rejecting cardiac allografts.
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.
Raisky
Olivier
O
Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Finland.
Nykänen
Antti I
AI
Krebs
Rainer
R
Hollmén
Maria
M
Keränen
Mikko A I
MA
Tikkanen
Jussi M
JM
Sihvola
Roope
R
Alhonen
Leena
L
Salven
Petri
P
Wu
Yan
Y
Hicklin
Daniel J
DJ
Alitalo
Kari
K
Koskinen
Petri K
PK
Lemström
Karl B
KB
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
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