Objectives: Previous reports suggest a role of platelet derived growth factor (PDGF) in the development of cardiac allograft vasculopathy (CAV). The pharmaceutical blockade of tyrosine kinases may alter the expression of different growth factor receptors: platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) and hereby play a role in the context of cardiac allograft vasculopathy. Therefore the aim of this study was to determine the impact of tyrosine kinase inhibition on the development of cardiac allograft vasculopathy in a mouse model.
Methods: Fully allogeneic mouse aortas from C57BL/6 mice (H2b) were abdominally transplanted into CBA mice (H2k). Recipients were treated with tyrosine kinase inhibitor nintedanib (60mg/kg/d) and sacrificed on day 14 for cytokine PCR analysis of the graft or on day 30 for (immuno-) histological measurements.
Results: Aortic grafts treated with tyrosine kinase inhibitor nintedanib showed significantly reduced neointima proliferation (33% ± 12% vs. 54% ± 13%) after 30 days. These findings go along with significantly reduced amounts of smooth muscle cells (SMC) (20% ± 9% vs. 42% ± 10%) within the neointima. Further immunofluorescence analysis revealed no relevant difference in the percentages of dendritic cells, macrophages and CD4+ T-cells within the neointima. Meanwhile, the expression of both PDGF receptor subtypes α and β was reduced within the neointima of the aortic grafts. Additionally, we found a reduced gene expression of the ligand PDGF-B, a mitogen for SMC, and of the pro-inflammatory CD40L.
Conclusion: PDGF receptor blockade via inhibition of receptor tyrosine kinases seems to be a promising way to prevent the development of cardiac allograft vasculopathy in a mouse model. We would speculate a direct inhibition of the migration and proliferation of smooth muscle cells with a resulting decrease of neointima formation as the mechanism of action.