Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury.
BACKGROUND
Chemokines expressed on atherosclerotic endothelium or deposited by activated platelets have been implicated in monocyte recruitment during atherogenesis and restenosis. Although the involvement of P-selectin in these processes is evident from studies in knockout mice, it has not been elucidated whether delivery of platelet chemokines requires P-selectin, thus serving as a P-selectin-dependent effector function.


RESULTS
Using immunofluorescence and laminar flow assays, we found that the deposition of the platelet-derived chemokine RANTES and monocyte arrest subsequently triggered by RANTES immobilized on inflamed endothelium are more efficient after preperfusion than after static preincubation of platelets and appear to depend on interactions of platelet but not endothelial P-selectin. This was revealed by the effects of P-selectin antibodies and comparison of P-selectin-deficient and wild-type platelets. Immunohistochemistry detected a substantial luminal expression of RANTES on neointimal lesions in wire-injured carotid arteries of apolipoprotein E (apoE)-deficient mice but not of mice with a combined deficiency in apoE and P-selectin (or platelet P-selectin). As assessed by histomorphometry, treatment of apoE-deficient mice with the RANTES receptor antagonist Met-RANTES markedly reduced neointimal plaque area and macrophage infiltration.


CONCLUSIONS
Our data suggest that RANTES deposition and subsequent monocyte arrest are promoted by platelet P-selectin and involved in wire-induced intimal hyperplasia, and that blocking RANTES receptors attenuates neointima formation and macrophage infiltration. This mechanism represents an important component explaining the protection against neointimal growth in P-selectin-deficient mice and may represent a novel approach to the treatment of restenosis or atherosclerosis by the administration of chemokine receptor antagonists.
Schober
Andreas
A
Department of Molecular Cardiovascular Research and Cardiology, Rheinisch-Westfälische Technische Hochschule Aachen, Germany.
Manka
David
D
von Hundelshausen
Philipp
P
Huo
Yuqing
Y
Hanrath
Peter
P
Sarembock
Ian J
IJ
Ley
Klaus
K
Weber
Christian
C
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001157:Arterial Occlusive Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000502:physiology*; D002340:Carotid Artery Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D008055:Lipids / Q000032:analysis; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D019007:P-Selectin / Q000235:genetics / Q000502:physiology*; D019713:Receptors, CCR5; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors
D001057:Apolipoproteins E; D018946:Chemokine CCL5; D008055:Lipids; D019007:P-Selectin; C108335:RANTES, Met-; D019713:Receptors, CCR5; D019707:Receptors, Chemokine