Background: Venous thromboembolism (VTE) is a frequent disease and may lead to chronic complications, including chronic thromboembolic pulmonary hypertension (CTEPH). Incomplete thrombus resolution is associated with residual vascular obstruction and vein wall fibrosis contributing to long term and irreversible sequelae. Fibrosis might result from endothelial-to-mesenchymal transition (EndMT), characterized by the loss of endothelial markers and the acquisition of mesenchymal markers.  TGF? is the most potent inducer of EndMT and has been involved in CTEPH. However, the molecular mechanisms implicated in EndMT in the context of VTE are unknown. We hypothesized that epigenetic processes regulate EndMT in VTE.
Aims: To determine if histone deacetylase 6 (HDAC6) regulates EndMT in response to TGF? during VTE.
Methods: We used both in vitro and in vivo models of venous thrombosis where HDAC6 was inactivated either by siRNA or pharmacological agents (TSC20b and tubastatin A) to study EndMT in endothelial cells.  Within group and treatment differences were analyzed using two-way ANOVA and Tukey?s multiple comparisons.
Results: Expression of the mesenchymal markers, calponin and ?-smooth muscle actin (SMA), was increased by TGF? and thrombin. Interestingly these changes were inhibited in presence of HDAC6 siRNA or TSC20b. Importantly, 7 and 17 days after induction of VTE in mice, thrombus size was smaller in the tubastatin A treated group compared to control.
Conclusion: We found that HDAC6 contributes to EndMT in venous thrombosis and impairs thrombus resolution. Thus, HDAC6 might represent an attractive therapeutic target for patients with a high risk of recurrent VTE.