Expression and Localization of Platelet-Derived Growth Factor Ligand and Receptor Protein During Acute and Chronic Rejection of Rat Cardiac Allografts

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Abstract
Background The molecular mechanisms of cardiac allograft vasculopathy (CAV) remain largely unknown. Using rat cardiac allografts, we examined by immunohistochemistry the expression and localization of platelet-derived growth factor ligand (PDGF-AA and -BB) and receptor (Rα and Rβ) proteins during acute and chronic rejection. Methods and Results In acute rejection, a prominent induction of both PDGF ligand and receptor proteins occurred in the interstitial mononuclear inflammatory cells ( P <.05), most of which were ED1-immunoreactive. PDGF-Rβ was also induced in the capillary endothelium ( P <.01). In cardiac allografts with severe intimal thickening, PDGF-AA expression was localized to the media and intima, whereas PDGF-BB expression was less prominent and was detected mainly in interstitial ED1-immunoreactive inflammatory cells. Double staining revealed that intimal cells expressing PDGF-AA were α-smooth muscle actin–positive but also α-smooth muscle actin–negative myofibroblast-like cells and to a lesser extent, ED1-immunoreactive cells. Both PDGF-Rα and -Rβ expression occurred in intimal, arterial endothelial, and interstitial mononuclear inflammatory cells. High-dose cyclosporin A (CsA) treatment significantly reduced both PDGF-AA and PDGF-Rα expression in intimal cells. Furthermore, linear regression analysis revealed that PDGF-AA, PDGF-Rα, and PDGF-Rβ expression in intimal cells and PDGF-BB expression in interstitial mononuclear inflammatory cells correlated with intimal thickening. Conclusions Alloimmune injury induces the expression of PDGF ligands, especially of PDGF-AA, in the graft vasculature and sufficient immunosuppression with CsA suppresses the expression of PDGF and inhibits the development of CAV. PDGF may have a substantial role in the regulation of smooth muscle cell migration and proliferation in an autocrine or paracrine manner during the development of CAV.