Platelet-endothelial cell interactions. (A) The healthy endothelium. The anti-adhesive phenotype of endothelial cells is maintained through 3 intrinsic pathways: the ecto-ADPase/CD39/NTPDase pathway, which metabolizes ADP, and the PGI₂ and NO pathways, which inhibit platelet activation through the stimulation of cAMP and cGMP production, respectively. (B) Endothelial activation in hyperlipemia. In a hyperlipidemic milieu, the endothelium becomes inflamed as a result of modified lipoprotein particles and reactive oxygen species (ROS) accumulating in the intima. This leads to the expression of adhesive ligands (VWF and P- and E-selectins) on the endothelium. (C) Platelet adhesion to the inflamed endothelium and platelet endothelial cross-talk. The expression of VWF and P-selectin on the endothelial surface supports platelet tethering and rolling. Subsequently, stable platelet adhesion occurs through fibrinogen-α_IIbβ₃ complexes binding to α_vβ₃ or ICAM-1 on endothelial cells. Adherent platelets secrete numerous bioactive substances that alter the chemotactic and adhesive properties of the endothelial cells. Platelet-derived IL-1β induces endothelial secretion of IL-6 and IL-8 and surface expression of ICAM-1, α_vβ₃, and MCP-1. Platelet CD40 ligand binds CD40 on endothelial cells, resulting in up-regulation of adhesive molecules (ICAM-1, VCAM-1, and E- and P-selectin), cytokine and TF release, and reduction in NO synthesis. Ecto ADPase indicates ecto-adenosine diphosphatase; NTPDase, nucleoside triphosphate diphosphohydrolase.