Critical Role of Platelet P-Selectin in the Response to Arterial Injury in Apolipoprotein-E–Deficient Mice

Abstract

Objective—Mice deficient in apolipoprotein-E (apoE^−/−) experience severe hypercholesterolemia that is exacerbated by a high-fat Western-type diet and atherosclerotic lesions spontaneously develop. In addition, we have reported that deficiency of P-selectin dramatically protects against neointimal lesion formation after arterial injury in apoE^−/−mice. To define the mechanism, bone marrow transplantation (BMT) after lethal irradiation was used to generate apoE^−/−chimeric mice deficient in platelet, but not endothelial, P-selectin.Methods and Results—Mice underwent vascular injury and were euthanized 4 weeks later. Absence of platelet P-selectin (pPS) expression in apoE^−/−mice after BMT was confirmed by flow cytometry and Western blot analysis. Lack of pPS in apoE^−/−mice resulted in a 62% reduction in neointimal area (45 000±27 000 versus 17 000±13 000 μm²,PP−/−BMT. Absence of pPS was also associated with a reduction in plaque neovascularization as compared with pPS-competent controls (0/8 versus 3/8,PConclusions—Lack of pPS significantly attenuates macrophage recruitment and neointimal lesion formation, indicating that pPS on platelets lining the vessel wall plays a critical role in inflammation after wire-withdrawal injury of the carotid artery in apoE^−/−mice.