Platelets in inflammation and atherogenesis

Abstract

Platelets represent an important linkage between inflammation, thrombosis, and atherogenesis. Inflammation is characterized by interactions among platelets, leukocytes, and ECs. These interactions trigger autocrine and paracrine activation processes that lead to leukocyte recruitment into the vascular wall. Platelet-induced chronic inflammatory processes at the vascular wall result in development of atherosclerotic lesions and atherothrombosis. This Review highlights the molecular machinery and inflammatory pathways used by platelets to initiate and accelerate atherothrombosis.Platelet interaction with endothelium At the site of vascular lesions, ECM proteins such as vWF and collagen are exposed to the blood.Platelet adhesion to the exposed matrix is considered to be the initial step in thrombus formation.Platelets adhere to vWF via the membrane adhesion receptor glycoprotein Ib/IX/V (GPIb/IX/V) (1) and to collagen via GPVI (2-4).This results in platelet activation and transformation of the integrin receptors α IIb β 3 (GPIIb/IIIa, fibrinogen receptor) (5, 6) and α 2 β 1 (collagen receptor) (4, 7), which firmly bind to the respective ECM components.Subsequently, platelets spread and form a surface for the recruitment of additional platelets via fibrinogen bridges between 2 α IIb β 3 receptors.In vitro studies with human ECs.In recent years, however, it has become increasingly evident that endothelial denudation is not an absolute prerequisite to allow platelet attachment to the arterial wall.The intact, nonactivated endothelium normally prevents platelet adhesion to the ECM.The adhesion receptors involved in platelet attachment to the subendothelial matrix, e.g., following rupture of an atherosclerotic plaque, have been well defined during the past decade; however, the molecular determinants that promote the interaction between platelets and endothelium are incompletely understood.Whereas endothelium normally controls platelet reactivity through inhibitory and modulating mechanisms involving COX-2, PGI 2 , or prostanoid synthetic systems, inflamed ECs develop properties that render them adhesive for platelets.In vitro studies showed that platelets adhere to the intact but activated human EC monolayer (8-10).Platelet adhesion to human umbilical vein ECs (HUVECs) is mediated by a GPIIb/IIIa-dependent bridging mechanism involving platelet-bound fibrinogen, fibronectin, and vWF (10).In HUVECs infected with herpes virus or stimulated with IL-1, platelet adhesion was effectively inhibited by antibodies to vWF or α IIb β 3 integrin, respectively (9,11,12).Furthermore, the involvement of the EC receptors ICAM-1, α v β 3 integrin, and GPIb in the binding of activated platelets to HUVECs has been described in vitro (10).In vivo studies of mouse models.Most in vitro studies have evaluated platelet-endothelium adhesion to human ECs under static conditions with limited attention to the dynamic situation in Nonstandard abbreviations used: CD40L, CD40 ligand; GP, glycoprotein; HUVEC, human umbilical vein EC; MCP-1, monocyte chemoattractant protein-1; PF4, platelet factor 4; uPAR, urokinase-type plasminogen activator receptor.