Adhesion Molecule P-Selectin and Vascular Cell Adhesion Molecule–1 in Enhanced Heart Allograft Arteriosclerosis in the Rat

Abstract

Background The increase of P-selectin on endothelial cells (EC) overlying human atherosclerotic plaques in classic atherosclerosis was recently established. We have previously shown that vascular cell adhesion molecule–1 (VCAM-1) is extensively expressed on EC of occluded arteries during accelerated transplant arteriosclerosis. In the present study, with the use of rat heart allografts under different doses of cyclosporine A (CsA), we investigated whether the expression of P-selectin is increased during chronic rejection and possibly coexpressed with VCAM-1 on EC. Methods and Results Rat cardiac allografts from DA donors to WF recipients were used. Without immunosuppression, these allografts show an irreversible rejection 7 days after transplantation. In the acute rejection model, syngeneic and allogeneic grafts were harvested 5 days after transplantation. In the chronic rejection model, allograft recipients received triple-drug immunosuppression, including azathioprine, methylprednisolone, and CsA in different doses. The grafts were removed 3 months after transplantation. During acute rejection, a significant expression of P-selectin ( P <.01) and VCAM-1 ( P <.05) on microvascular endothelia, but not on arteries, was noticed. During intense chronic rejection (5 mg/kg CsA), arterial EC expressed P-selectin ( P <.01) and VCAM-1 ( P <.05) extensively. The expression of tumor necrosis factor–α, a cytokine inducing both P-selectin and VCAM-1 expression, was upregulated in vascular medial cells ( P <.05), in intimal cells ( P <.01), and in interstitial mononuclear cells ( P <.05). Linear regression analysis revealed a significant correlation between arterial P-selectin ( P <.01) and VCAM-1 ( P <.01) expression and the intensity of intimal thickening. Also, a significant correlation and coexpression of P-selectin and VCAM-1 in epicardial arteries was demonstrated ( P <.05). Conclusions The early expression of P-selectin on microvascular EC during acute rejection may be the basis of cell adhesion and infiltration into the site of inflammation. During chronic rejection, the intensity of arterial intimal thickening was significantly correlated with the intensity of P-selectin expression on EC, in addition to that of previously reported VCAM-1 expression. Thus, P-selectin may have a crucial role in the pathogenesis of chronic rejection in the vascular wall, augmenting the immune-mediated injury against the allograft.