--- title: "HDAC6 regulates endothelial-to-mesenchymal transition and delays thrombus resolution in venous thr" id: "biorxiv-22-hdac6-is-a-novel-regulator-of-endothelial-to-mesenchymal-transition-in-venous" canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-22-hdac6-is-a-novel-regulator-of-endothelial-to-mesenchymal-transition-in-venous" content_type: "clinical_feed_article" specialty: "Hematology" source_name: "bioRxiv (Biomedical Preprints)" source_url: "https://www.biorxiv.org/content/10.64898/2026.08.27.747544v1?rss=1" published_at: "2026-09-01T12:00:00.000Z" evidence_level: "Verified Feed" license: "CC-BY-NC-4.0 / Informational Use" --- # HDAC6 regulates endothelial-to-mesenchymal transition and delays thrombus resolution in venous thr ## Provenance & Clinical Metadata - **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-22-hdac6-is-a-novel-regulator-of-endothelial-to-mesenchymal-transition-in-venous - **Specialty:** [Hematology](https://medichelpline.com/clinical-feed/hematology.md) - **Primary Source:** bioRxiv (Biomedical Preprints) - **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.27.747544v1?rss=1) - **Published At:** 2026-09-01T12:00:00.000Z - **Evidence Rating:** Verified Feed ## Executive GIST (TL;DR) - Venous thromboembolism (VTE) involves thrombus formation and vein wall remodeling; fibrosis may result from **endothelial-to-mesenchymal transition (EndMT)** driven by loss of endothelial markers and gain of mesenchymal markers. - Transforming growth factor beta (**TGFβ**) is a potent inducer of EndMT and impairs thrombus resolution in chronic thromboembolic pulmonary hypertension; molecular regulators of TGFβ signaling in VTE were previously unclear. - The authors hypothesized that epigenetic regulators control TGFβ signaling in endothelial cells and promote EndMT and vascular fibrosis. - The study investigated the role of histone deacetylase 6 (**HDAC6**) using in vitro endothelial cell experiments and an in vivo experimental VTE model, and analyzed public RNAseq datasets to support findings. - In vitro, endothelial cells treated with TGFβ and thrombin upregulated mesenchymal markers calponin and **transgelin**; pharmacological inhibition of HDAC6 with TCS20b prevented these increases. - TGFβ effects were mediated via ERK1/2 activation and HDAC6 activation according to the reported molecular analyses. - In vivo, treatment with the specific HDAC6 inhibitor **tubastatin A** reduced thrombus size seven days after surgery compared with controls; treatment durations reported ranged from 7 to 21 days. - Reduced expression of the EndMT marker transgelin in endothelial cells was observed in animals treated with HDAC6 inhibition relative to controls. - The splice isoform **FN1-EDA** was shown to be associated with EndMT, regulated by HDAC6 in vitro, linked to thrombosis in the analyzed RNAseq dataset, and potentially associated with recurrent DVT in patients. - Statistical analyses used two-way ANOVA with Tukey’s multiple comparisons for within-group and treatment differences. - The authors conclude that **HDAC6** regulates EndMT in venous thrombosis, impairs thrombus resolution, and controls expression of FN1-EDA, suggesting HDAC6 as a potential therapeutic target to reduce risk of recurrent VTE. - Funding sources and competing interests: the study declared funding by Fondation du Souffle and Fédération française de cardiologie; authors declared no competing interests. ## Clinical Analysis & Structured Key Points Background: Venous thromboembolism (VTE), which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), is a frequent disease associated with thrombus formation and vein wall remodeling. Hence, fibrosis might result from endothelial-to-mesenchymal transition (EndMT), characterized by the loss of endothelial markers and the acquisition of mesenchymal markers. In chronic thromboembolic pulmonary hypertension, transforming growth factor (TGF{beta}), the most potent inducer of EndMT, impairs thrombus resolution. However, the molecular mechanisms implicated in TGF[beta] signaling in the context of VTE are unknown. We hypothesized that epigenetic processes regulate the TGF{beta} signaling pathway in endothelial cells promoting EndMT and vascular fibrosis. Aims: To determine if the histone deacetylase 6 (HDAC6) regulates the TGF{beta} signaling pathway in endothelial cells promoting EndMT and delays venous thrombosis. Methods: To study the role of HDAC6 in EndMT, endothelial cells were treated with a pharmacological inhibitor (TCS20b) and incubated with TGF{beta} and thrombin for 2, 3, and 5 days. Real time PCR and Western blot were performed to analyze endothelial and mesenchymal marker expression and TGF{beta} signaling. An experimental model of VTE was used to study the role of HDAC6 on thrombus size overtime. Animals were treated or not with a specific HDAC6 inhibitor (tubastatin A) for 7 to 21 days. Analysis of RNAseq data sets publicly available were used to confirm our main results. Within group and treatment differences were analyzed using two-way ANOVA and Tukeys multiple comparisons. Results: Expression of the mesenchymal markers, calponin and transgelin, was increased by TGF{beta} and thrombin. Interestingly these changes were inhibited in presence of TCS20b. TGF{beta} mediated these effects through ERK1/2 and HDAC6 activation. Inhibition of HDAC6 in vivo reduced thrombus size 7 days after surgery compared to controls. This was associated with reduced expression of the EndMT marker transgelin in endothelial cells compared to the control animals. We found that FN1-EDA expression was associated with EndMT and regulated by HDAC6 in vitro. This marker was also associated with thrombosis in the RNAseq data set that we analyzed and potentially in patients with recurrent DVT. Conclusion: We found that HDAC6 regulates EndMT in venous thrombosis and impairs thrombus resolution. HDAC6 also regulates expression FN1-EDA that appears to be a strong marker associated with DVT and DVT recurrence. 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