Combined vascular endothelial growth factor and platelet-derived growth factor inhibition in rat cardiac allografts: beneficial effects on inflammation and smooth muscle cell proliferation.
BACKGROUND
Perivascular inflammation and subsequent smooth muscle cell (SMC) proliferation are central in the development of cardiac allograft arteriosclerosis. We examined the effect of combined inhibition of proinflammatory vascular endothelial growth factor (VEGF) and SMC mitogen platelet-derived growth factor (PDGF) in rat cardiac allografts.


METHODS
Heterotopic cardiac transplantations were performed between fully major histocompatibility mismatched rat strains receiving cyclosporine A immunosuppression. In situ hybridization and immunohistochemistry were performed to examine VEGF and PDGF ligand and receptor (R) expression. Protein tyrosine kinase inhibitors PTK787 and imatinib were used to inhibit VEGFR and PDGFR activity, respectively. Rat coronary artery SMC migration and proliferation assays were used to examine the effect of VEGF and PDGF and tyrosine kinase inhibitors in vitro.


RESULTS
Both ligand and receptor expression of VEGF and PDGF were detected in chronically rejecting allografts. In vitro, PDGF-BB mediated rat coronary artery SMC migration and proliferation was completely inhibited with imatinib and partially with PTK787. In vivo, combined treatment with PTK787 and imatinib significantly reduced the formation of neointimal lesions in arteries of cardiac allografts at 8 weeks, producing a greater effect than either drug alone. PTK787, in contrast with imatinib, reduced the number of ED1 macrophages and PDGF-B immunoreactivity in the allografts at 4 weeks.


CONCLUSIONS
Blocking VEGF and PDGF receptor signaling in cardiac allografts has distinctive effects on inflammation and SMC proliferation, suggesting that targeting both inflammation and pathologic vascular remodeling may be needed to inhibit cardiac allograft arteriosclerosis.
Nykänen
Antti I
AI
Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, P.O. Box 21, Haartmaninkatu 3, FIN-00014 University of Helsinki, Finland. Antti.Nykanen@Helsinki.Fi
Krebs
Rainer
R
Tikkanen
Jussi M
JM
Raisky
Olivier
O
Sihvola
Roope
R
Wood
Jeanette
J
Koskinen
Petri K
PK
Lemström
Karl B
KB
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control; D001549:Benzamides; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D000068877:Imatinib Mesylate; D007249:Inflammation; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D011183:Postoperative Complications / Q000473:pathology; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D017479:Receptors, Platelet-Derived Growth Factor / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D020533:Angiogenesis Inhibitors; D001549:Benzamides; D010793:Phthalazines; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C404768:vatalanib; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2