Expression and localization of platelet-derived growth factor ligand and receptor protein during acute and chronic rejection of rat cardiac allografts.

Abstract

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 (R alpha and R beta) proteins during acute and chronic rejection. 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-R beta 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 alpha-smooth muscle actin-positive but also alpha-smooth muscle actin-negative myofibroblast-like cells and to a lesser extent, ED1-immunoreactive cells. Both PDGF-R alpha and -R beta expression occurred in intimal, arterial endothelial, and interstitial mononuclear inflammatory cells. High-dose cyclosporin A (CsA) treatment significantly reduced both PDGF-AA and PDGF-R alpha expression in intimal cells. Furthermore, linear regression analysis revealed that PDGF-AA, PDGF-R alpha, and PDGF-R beta expression in intimal cells and PDGF-BB expression in interstitial mononuclear inflammatory cells correlated with intimal thickening. 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.