Published online before print November 4, 2004, doi: 10.1161/01.RES.0000149518.86865.3e
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Crucial Role of the CCL2/CCR2 Axis in Neointimal Hyperplasia After Arterial Injury in Hyperlipidemic Mice Involves Early Monocyte Recruitment and CCL2 Presentation on Platelets
From the Department of Molecular Cardiovascular Research (A.S., A.Z., E.A.L., P.v.H., S.K., C.W.), Department of Cardiology (A.S., A.Z., P.v.H., C.W.), University Hospital, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany; and the Section of Molecular Genetics and Microbiology (W.A.K.), Institute for Cellular and Molecular Biology, University of Texas, Austin. The present address for A.S. is Division of Cardiology, Medizinische Poliklinik, University Hospital, Munich, Germany.
Correspondence to Dr Christian Weber, Kardiovaskuläre Molekularbiologie, Universitätsklinikum Aachen, Pauwelsstraße 30, 52057 Aachen, Germany. E-mail cweber{at}ukaachen.de
Monocyte chemoattractant protein-1 (also known as CC chemokine ligand 2 [CCL2]) and its receptor CC chemokine receptor 2 (CCR2) play a central role in the inflammatory response and neointimal formation after vascular injury. In the context of hyperlipidemia, this appears to involve neointimal monocyte infiltration. Hence, we investigated the function of the CCL2/CCR2 axis in early monocyte recruitment to injured arteries. Wire-induced injury of the carotid artery in apoE–/– mice caused a rapid increase of JE/CCL2 protein in the vessel wall peaking at 24 hours after injury, whereas serum JE/CCL2 was increased solely at 6 hours and blood cell-associated levels were unaltered, as demonstrated by enzyme-linked immunosorbent assay. Immunohistochemistry revealed intense staining for JE/CCL2 in smooth muscle cells (SMCs) and in association with platelets adherent to the denuded vessel wall 24 hours after injury. In vitro, exogenous or SMC-derived JE/CCL2 binds to the platelet surface and triggers monocyte arrest on adherent platelets but not on SMCs in flow assays. Accordingly, monocyte arrest in ex vivo perfused apoE–/– carotid arteries isolated 24 hours after injury was profoundly inhibited by pretreatment with a JE/CCL2 antibody. In CCR2–/–/apoE–/– mice, neointimal plaque area was reduced by 47% compared with CCR2+/+/apoE–/– mice. Moreover, CCR2 deletion markedly decreased neointimal macrophage content while expanding SMC content. Vascular JE/CCL2 expressed by SMCs and immobilized by adherent platelets after endothelial denudation is crucial for mediating early monocyte recruitment to injured arteries in hyperlipidemic mice. This mechanism may explain reduced neointimal macrophage infiltration and lesion formation in CCR2-deficient apoE–/– mice.
Key Words: inflammation • restenosis • platelets • vascular biology • monocyte chemoattractant protein-1
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