Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury.

Abstract

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.

METHODS AND 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.

• Authors: Andreas Schober, David Manka, Philipp von Hundelshausen, Yuqing Huo, Peter Hanrath, Ian J Sarembock, Klaus Ley, Christian Weber
• Journal: Circulation (Circulation) Vol. 106 Issue 12 Pg. 1523-9 (Sep 17 2002) ISSN: 1524-4539 [Electronic] United States
• PMID: 12234959 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apolipoproteins E
• Chemokine CCL5
• Lipids
• P-Selectin
• RANTES, Met-
• Receptors, CCR5
• Receptors, Chemokine

Topics

• Animals
• Apolipoproteins E (genetics)
• Arterial Occlusive Diseases (etiology, metabolism, pathology)
• Blood Platelets (physiology)
• Carotid Artery Diseases (etiology, metabolism, pathology)
• Cell Line
• Cell Movement
• Cells, Cultured
• Chemokine CCL5 (analogs & derivatives, analysis, metabolism, pharmacology, physiology)
• Endothelium, Vascular (physiology)
• Humans
• Lipids (analysis)
• Macrophages (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (physiology)
• P-Selectin (genetics, physiology)
• Receptors, CCR5
• Receptors, Chemokine (antagonists & inhibitors)