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.


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.
Manka
David
D
Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Va 22908-0158, USA.
Forlow
S Bradley
SB
Sanders
John M
JM
Hurwitz
Debra
D
Bennett
Daniel K
DK
Green
Samuel A
SA
Ley
Klaus
K
Sarembock
Ian J
IJ
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001772:Blood Cell Count; D001792:Blood Platelets / Q000502:physiology*; D016026:Bone Marrow Transplantation; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology*; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000293:injuries; D005260:Female; D008074:Lipoproteins / Q000097:blood; D008264:Macrophages / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera; D013314:Stress, Mechanical; D017539:Tunica Intima / Q000473:pathology
D001057:Apolipoproteins E; D008074:Lipoproteins; D019007:P-Selectin