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 microm2, 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.