Background: Venous thromboembolism (VTE), which encompasses pulmonary embolism and deep vein thrombosis, is a frequent disease that is associated with vein wall fibrosis. Endothelial cells undergo phenotypical changes named the endothelial to mesenchymal transition (EndMT), characterized by the loss of endothelial markers and the acquisition of mesenchymal markers leading to fibrosis. Transforming growth factor (TGFβ) is the most potent inducer of EndMT. A recent study showed that in chronic thromboembolic pulmonary hypertension, TGFβ induced EndMT and impaired thrombus resolution. In addition, epigenetic mechanisms regulate EndMT. However, the molecular mechanisms implicated in TGFβ signalling in the context of venous thromboembolism are unknown. We hypothesized that epigenetic processes regulate the TGFβ signaling pathway in endothelial cells promoting EndMT and recurrent thrombosis.

Aims: The aim of this study was to test if EndMT is regulated by epigenetic mechanisms in recurrent thrombosis.

Methods: Endothelial cells were treated with TGFβ, thrombin or both during 72 hours. To study the role of histone deacetylase (HDAC) in EndMT, endothelial cells were also incubated in presence of vorinostat, an HDAC inhibitor. Real time PCR and western-blot were performed to analyze endothelial and mesenchymal marker expression.

Results: Expression of VE-cadherin was not modified by TGFβ and thrombin treatment. Calponin expression was increased by TGFβ and thrombin even in the presence of vorinostat. Interestingly, α-smooth muscle actin and collagen expression was increased by thrombin and TGFβ and inhibited by vorinostat treatment.

Conclusions: We found that treatment of endothelial cells with TGFβ and thrombin is associated with EndMT. Our preliminary data suggest that HDACs contribute to EndMT. HDAC may repress the expression of antifibrotic factors in endothelial cells during venous thrombosis. The discovery of biomarkers or new therapeutic targets would be instrumental in guiding decisions of treatment for patients with a high risk of recurrent VTE.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/epigenetic-regulation-of-endothelial-dysfunction-in-venous-thromboembolism/