Venous thromboembolism (VTE) carries a high risk of morbidity and mortality. Understanding the mechanisms of venous
thrombus formation and resolution is critical for improving VTE management. AKT2
kinase is essential for platelet activation and arterial
thrombosis. In this study, we examined the role of AKT2 in
venous thrombosis in a mouse model of
venous thrombosis induced by inferior vena cava (IVC)
ligation. We observed an induction of AKT2 expression in the ligated IVC of wild-type (WT) mice. Interestingly, although the initial
thrombus size of the ligated IVC was similar between Akt2-/- mice and WT mice,
thrombus resolution was delayed in the ligated IVC of Akt2-/- mice. Compared with the ligated IVC of WT mice, the ligated IVC of Akt2-/- mice displayed decreased levels of
thrombomodulin (TM) and increased levels of
tissue factor (TF), apoptosis, and necroptosis. In addition, intrathrombotic endothelial cells in the ligated IVC of Akt2-/- mice failed to form small vessels, resulting in impaired recanalization and
thrombus resolution. TGF-β signaling activation and fibrotic remodeling were increased in the
thrombus and vein wall of the ligated IVC of Akt2-/- mice. We further investigated the AKT2-mediated regulation of
coagulation factors in endothelial cells and found that
forkhead box protein O1 (FOXO1), a target of AKT, enhanced TF and inhibited TM expression. By inhibiting FOXO1, AKT2 suppressed TF expression while increasing TM expression. Our findings indicate that AKT2 may protect endothelial cells against cell death, regulate endothelial-mediated coagulation homeostasis, and promote intrathrombotic recanalization and
thrombus resolution in
venous thrombosis. These observations suggest dynamic roles of AKT2 in venous
thrombus formation and resolution.