Homocysteine activates endothelial TP receptor to promote von Willebrand factor secretion and thrombosis.

Abstract

Hyperhomocysteinemia (HHcy), characterized by elevated plasma homocysteine (Hcy) levels, is a recognized risk factor for thrombosis and an independent contributor to acute coronary syndrome, although its underlying mechanisms are not fully understood. The current study is to investigate the impact of HHcy on arterial thrombosis and the underlying mechanisms. In this study, we established an HHcy mouse model using a high-methionine diet and found that HHcy significantly accelerated thrombosis. We identified that Hcy enhanced von Willebrand factor (vWF) secretion from endothelial cells, leading to increased FVIII-vWF binding and platelet adhesion. Moreover, we observed a significant positive correlation between vWF and Hcy levels in the plasma of 150 patients with acute coronary syndrome. Mechanistically, GPCR screening revealed that Hcy-induced increase in vWF levels was mediated by activating the thromboxane prostanoid receptor (TPr) on endothelial cells. Hcy might function as an endogenous ligand binding to TPr and subsequently activated the Gαq-PLC-Capathway to promote vWF secretion. Pharmacological inhibition or endothelial-specific deletion of TPr effectively reduced plasma vWF levels and protected against HHcy-related thrombosis. Our findings underscored the pivotal role of TPr in mediating Hcy-induced procoagulant states and suggested that targeting the TPr signaling pathway could be a promising therapeutic strategy for treating HHcy-related thrombosis.