Lemström K B, Koskinen P K
Transplantation Laboratory, University of Helsinki, and Helsinki University Central Hospital, Finland.
Circulation. 1997 Aug 19;96(4):1240-9. doi: 10.1161/01.cir.96.4.1240.
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.
