RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium

Background-Circulating platelets and chemoattractant proteins, such as the CC chemokine RANTES, contribute to the activation and interaction of monocy tes and endothelium and may thereby play a pivotal role in the pathogenesis of inflammatory and atherosclerotic disease. Methods and Results-The binding of RANTES to human endothelial cells was de tected by ELISA or immunofluorescence after perfusion with platelets or exp osure to their supernatants. Monocyte arrest on endothelial monolayers or S urface-adherent platelets was studied with a parallel-wall flow chamber and video microscopy, We show that RANTES secreted by thrombin-stimulated plat elets is immobilized on the surface of inflamed microvascular or aortic end othelium and triggers shear-resistant monocyte arrest under flow conditions , as shown by inhibition with the RANTES receptor antagonist Met-RANTES or a blocking RANTES antibody. Deposition of RANTES and its effects requires e ndothelial activation, eg, by interleukin-1 beta, and is not supported by v enous endothelium or adherent platelets. Immunohistochemistry revealed that RANTES is present on the luminal surface of carotid arteries of apolipopro tein E-deficient mice with early atherosclerotic lesions after wire-induced injury or cytokine exposure. In a mechanistic model of atherogenesis, mono cyte adherence on endothelium covering such lesions was studied in murine c arotid arteries perfused ex vivo, showing that the accumulation of monocyti c cells in these carotid arteries involved RANTES receptors. Conclusions-The deposition of RANTES by platelets triggers shear-resistant monocyte arrest on inflamed or atherosclerotic endothelium. Delivery of RAN TES by platelets may epitomize a novel principle relevant to inflammatory o r atherogenic monocyte recruitment from the circulation.