Objective
Deep vein thrombosis (DVT) and pulmonary embolism are frequent causes of morbidity and mortality. We wished to determine whether plasma high density lipoprotein (HDL), which inversely correlates with the risk of cardiovascular events, affects DVT.
Methods and Results
Using a murine DVT model of inferior vena cava stenosis, we demonstrate that deficiency of the HDL receptor, scavenger receptor class B type I (SR-BI), promotes venous thrombosis. As SR-BI−/− mice have increased plasma cholesterol levels and abnormal HDL particles, we tested SR-BI−/− mice with an SR-BI liver transgene that normalizes both parameters. These mice also exhibited increased susceptibility to DVT, indicating a protective role of extrahepatic SR-BI. Mice lacking the major HDL apolipoprotein apoA-I or eNOS (a downstream target of endothelial SR-BI signaling) also had a pro-thrombotic phenotype. Intravenous infusion of human apoA-I, an HDL component and SR-BI ligand, prevented DVT in wild-type but not SR-BI−/− or eNOS−/− mice, suggesting that its effect is mediated by SR-BI and eNOS. Intravenous apoA-I infusion abolished histamine-induced platelet-endothelial interactions, which are important for DVT initiation.
Conclusion
An apoA-I (HDL) - SR-BI - eNOS axis is highly protective in DVT and may provide new targets for prophylaxis and treatment of venous thrombosis.