Resolvin D2 attenuates platelet activation and thrombosis via the GPR18 receptor

Arterial thrombotic events, including acute coronary syndromes, remain the leading cause of morbidity and mortality worldwide. Platelet activation plays a crucial role in arterial thrombosis. The resolution of inflammation is an actively regulated physiological process driven by specialized pro-resolving mediators (SPMs). Resolvin D2 (RvD2), a core endogenous lipid mediator derived from docosahexaenoic acid (DHA), exhibits established protective effects in maintaining cardiovascular homeostasis and delaying atherosclerosis. However, the roles of RvD2 and its receptor GPR18 in platelet activation and arterial thrombosis remain largely unknown. In this study, we evaluated the effects of RvD2 on platelet activation and thrombosis using in vitro platelet function assays and an in vivo thrombosis model. In vitro assays demonstrated that RvD2 concentration-dependently (50, 100, 500 pg/mL) inhibited human platelet aggregation induced by thrombin, collagen, and ADP, and reduced ATP release induced by thrombin and collagen. RvD2 pretreatment significantly decreased the spreading area of platelets on immobilized fibrinogen and delayed clot retraction. Furthermore, the putative GPR18 antagonist O-1918 successfully abolished the RvD2-mediated inhibition of aggregation and clot retraction. Using wild-type (WT) and Gpr18 knockout (Gpr18^-/-) mice, we confirmed that RvD2 exerted its inhibitory effects on aggregation and ATP release only in WT mice. In a FeCl₃-induced mesenteric artery thrombosis model, intravenous administration of RvD2 (0.5 μg/kg) significantly prolonged the time to first microthrombus formation (>20 μm) and the final vessel occlusion time in WT mice, whereas this antithrombotic protection was entirely lost in Gpr18^-/- mice. Finally, clinical cohort analysis of 77 patients with coronary heart disease (CHD) revealed that baseline plasma RvD2 levels were negatively correlated with ADP- and collagen-induced platelet reactivity. Our findings demonstrate that RvD2 attenuates platelet activation and thrombosis via the GPR18 receptor, and that the platelet hyperreactivity observed in patients with CHD may be associated with reduced plasma RvD2 levels.