Critical role of platelet P-selectin in the response to arterial injury in apolipoprotein-E-deficient mice

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 mum(2), P < 0.000001) and a 30% reduction (P < 0.02) in macrophage infiltration, compared with control apoE(-/-) BMT. Absence of pPS was also associated with a reduction in plaque neovascularization as compared with pPS-competent controls (0/8 versus 3/8, P < 0.05). Conclusions - 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.