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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1124.)
© 2004 American Heart Association, Inc.

Thrombosis

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

David Manka; S. Bradley Forlow; John M. Sanders; Debra Hurwitz; Daniel K. Bennett; Samuel A. Green; Klaus Ley; Ian J. Sarembock

From the Departments of Biomedical Engineering (D.M., S.B.F, K.L.), Cell Biology (S.A.G.), Internal Medicine Cardiovascular Division (J.M.S., D.H., D.K.B., I.J.S.), and Cardiovascular Research Center (K.L., I.J.S.), University of Virginia Health System, Charlottesville, Va.

Correspondence to Dr Ian J. Sarembock, Cardiovascular Division, University of Virginia Health System, Box 800158, Charlottesville, VA 22908-0158. E-mail ijs4s{at}virginia.edu

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, 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.

Lack of platelet P-selectin reduced neointima formation and macrophage infiltration by 62% and 30%, respectively, versus control, and protected against the development of plaque neovascularization in wire-injured carotid arteries of apoE-deficient mice. This indicates that platelet P-selectin plays a critical role in inflammation after vascular injury.

Key Words: inflammation • atherosclerosis • cell adhesion molecules • angiogenesis • carotid arteries

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