Role of platelet-derived growth factor in allograft vasculopathy

To test the hypothesis that platelet-derived growth factor (PDGF) accelerates the formation of allograft vascular disease. Allograft vasculopathy, characterized by myointimal hyperplasia of the coronary arteries in the transplanted heart, is the most common cause of late graft failure and death in heart transplant recipients. The cause of the process is unclear, and no treatment exists. PDGF has been implicated in alterations in vascular endothelial biology and in vascular restenosis, but the role of PDGF in allograft vasculopathy has not been explored. An orthotopic heart transplant model was established in the rat mismatched at one class II locus using the PVGR8 and PVGR23 strains. No immunosuppressive regimen was used. Six treatment groups (PDGF-A, PDGF-A antibody, and PDGF-A receptor antibody) using 10 rats per group were examined. An untreated group of 10 rats manifesting chronic rejection as well as the native hearts 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 animals were killed after 50 days; transplanted and native hearts were removed and coronary arteries were examined morphometrically. Smooth muscle proliferation was confirmed by immunohistochemistry. Statistical analysis was performed using multivariate analysis of variance. Coronary myointimal hyperplasia was seen in the chronic rejection group. The PDGF-A groups showed significant myointimal hyperplasia. Administration of PDGF-A antibody did not attenuate the process. Administration of PDGF-A receptor antibody at 1 ng/dL resulted in reduction of the hyperplasia, and 10 ng/dL significantly attenuated the process. This study establishes a cause-and-effect relation between PDGF-A and coronary myointimal hyperplasia in the rat transplant model. Blockade of the PDGF-A receptor clearly attenuates the process, indicating a potential mode of therapy to be explored.