Abstract
Background. Signal transduction through the platelet-derived growth factor (PDGF)/PDGF-receptor (PDGFR) system has been linked to vascular smooth muscle cell migration and proliferation leading to allograft vasculopathy. This study describes the effect of the tyrphostin AG-1295, a specific PDGFR tyrosinekinase inhibitor, on neointimal formation in this disease. Methods and Results. Rat aortic allografts transplanted from dark agouti (RT1av1) donors to Wistar-Furth (RT1u) recipients were assessed in a new treatment model for local drug delivery from polymeric carrier matrices precoated with AG-1295. Matrices were wrapped around the graft immediately after transplantation. The recipients received no background immunosuppression. At day 80 posttransplantation, intimal thickness in AG-1295-treated grafts was reduced when compared to controls (11.8±9.1% intimal thickness vs. 23.7±6.4% intimal thickness; P=0.042). This finding corresponded to inhibition of intimal PDGFR-β expression in AG-1295-treated grafts at day 20 posttransplantation (P=0.029 vs. allogeneic controls). Conclusions. The tyrphostin AG-1295 reduces neointimal formation in aortic allograft vasculopathy by inhibition of PDGFR-β-triggered tyrosine phosphorylation. Local drug release of specific tyrosine-kinase inhibitors from perivascularly co-implanted polymeric carrier matrices is effective in the prophylaxis of allograft vasculopathy under selected experimental conditions.
Original language | English |
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Pages (from-to) | 1335-1341 |
Number of pages | 7 |
Journal | Transplantation |
Volume | 74 |
Issue number | 9 |
DOIs | |
State | Published - 15 Nov 2002 |