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.

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…This signalling may result in the upregulation of selectins and integrins on the surface of platelets , enabling platelets to bind and activate circulating leukocytes. A relationship between platelet P-selectin expression and platelet-leukocyte endothelial arrest after chemokine activation has since been revealed in several studies (Schober et al, 2002;Huo et al, 2003;Von Hundelshausen et al, 2005).…”

“…In this regard, experimental models of disease have provided evidence for a requirement of platelets in pulmonary eosinophil and lymphocyte recruitment in rabbits, guineapigs and mice in models of allergic inflammation (LellouchTubiana et al, 1988;Coyle et al, 1990;Pitchford et al, 2003Pitchford et al, , 2005; and neutrophil and monocyte recruitment in atherosclerosis (Arber et al, 1991;Neumann et al, 1997;Hayward et al, 1999) and RA (Schmitt-Sody et al, 2005). This phenomenon requires intact platelets expressing mediators on the cell surface, and in common with the occurrence of leukocyte recruitment in inflammatory diseases, platelet Pselectin is of particular importance (Diacovo et al, 1996a, b;Schober et al, 2002;Huo et al, 2003;Pitchford et al, 2005). With regard to asthma, this mechanism has been confirmed by various in vitro studies, revealing eosinophil attachment to inflamed endothelium is greatly enhanced in the presence of platelets taken from asthmatic patients, and P-selectin expressed by platelets is responsible for platelet-eosinophil interactions in particular (Jawien et al, 2002;Ulfman et al, 2003).…”

“…Antagonists for specific chemokine receptors may be advantageous, for example the targeting of platelet CCR3 and CCR4 might be of benefit in treating asthmatics (Gonzalo et al, 1999;Sekiya et al, 2000), while the targeting of RANTES may be beneficial in the treatment of atherosclerosis since platelet-derived RANTES deposited on the surface of endothelial cells is necessary for monocyte accumulation (Von Hundelshausen et al, 2005). Indeed, RANTES receptor antagonists inhibit the infiltration of macrophages, and importantly, reduce neointima formation in ApoE-deficient mice (Schober et al, 2002;Huo et al, 2003).…”

Plaque, Platelets, and Plug – The Pathogenesis of Acute Coronary Syndrome

“…RANTES, secreted by activated platelets, triggers monocyte arrest and recruitment under flow conditions in vitro and in perfused carotid arteries (von Hundelshausen et al, 2001). Platelet P-selectin is important mediator of RANTES upregulation, indicates that RANTES is secreted during platelet rolling to endothelial cells (Schober et al, 2002). In atherosclerotic lesions and injury of apolipoprotein-E deficient mice, RANTES is expressed on endothelial cells (von Hundelshausen et al, 2001).…”

“…Endothelial cells should have been modified by IL-1 , in order to receive the deposition of RANTES (Weyrich et al, 2002). Taken together, platelet-generated RANTES involves in atherosclerosis early in the beginning and more prominently in the plaque progression by modulating intimal hyperplasia and monocyte recruitment (Schober et al, 2002). Initial knowledge of ENA-78 activity is that this CXC chemokine superfamily member is synthesized and secreted by activated endothelial cells which give a proadhesive activity for neutrophils (Walz et al, 1997).…”