Chronic rejection (CR), which is characterized histologically by progressive graft arteriosclerosis, remains a significant barrier to the long-term survival of a graft. Sildenafil has been shown to protect vascular endothelial cells. In this study, we found that sildenafil significantly reduces the thickness of transplant vascular intima in a rat aortic transplant model. Moreover, sildenafil dramatically decreased the expression of transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), and α-smooth muscle actin (α-SMA) in the grafted aortas and increased the concentrations of cyclic guanosine monophosphate (cGMP) and endothelial nitric oxide synthase (eNOS) in serum. Furthermore, the ratio of regulatory T (Treg) cells and the expression of FoxP3 were increased, and the ratio of Th17 cells was decreased in the sildenafil-treated group. These results demonstrate that sildenafil enhances nitric oxide (NO) signaling by increasing the availability of cGMP, leading to an increase in the ratio of Treg/Th17 cells to attenuate transplant arteriosclerosis in a rat aortic transplant model.
Keywords: Chronic rejection; Th17/Treg; cGMP; eNOS; graft arteriosclerosis; sildenafil.