Role of platelet-derived growth factor in allograft vasculopathy

Objective To test the hypothesis that platelet-derived growth factor (PDGF) accelerat es the formation of allograft vascular disease. Summary Background Data Allograft vasculopathy, characterized by myointimal hyperplasia of the coro nary arteries in the transplanted heart, is the most common cause of late g raft failure and death in heart transplant recipients. The cause of the pro cess is unclear, and no treatment exists, PDGF has been implicated in alter ations in vascular endothelial biology and in vascular restenosis, but the role of PDGF in allograft vasculopathy has not been explored. Methods An orthotopic heart transplant model was established in the rat mismatched at one class II locus using the PVGR8 and PVGR23 strains. No immunosuppress ive regimen was used. Six treatment groups (PDGF-A, PDGF-A antibody, and PD GF-A receptor antibody) using 10 rats per group were examined. An untreated group of 10 rats manifesting chronic rejection as well as the native heart s were used as controls. PDGF-A at 1 ng/dL (10 rats) or 10 ng/dL (10 rats) was administered intraperitoneally to each transplant group. Similar groups were treated with PDGF-A antibody and PDGF-A receptor antibody. The animal s were killed after 50 days; trans planted and native hearts were removed a nd coronary arteries were examined morphometrically. Smooth muscle prolifer ation was confirmed by immunohistochemistry. Statistical analysis was perfo rmed using multivariate analysis of variance. Results Coronary myointimal hyperplasia was seen in the chronic rejection group. Th e PDGF-A groups showed significant myointimal hyperplasia. Administration o f PDGF-A antibody did not attenuate the process. Administration of PDGF-A r eceptor antibody at 1 ng/dL resulted in reduction of the hyperplasia, and 1 0 ng/dL significantly attenuated the process. Conclusions This study establishes a cause-and-effect relation between PDGF-A and coron ary myointimal hyperplasia in the rat transplant model. Blockade of the PDG F-A receptor clearly attenuates the process, indicating a potential mode of therapy to be explored.