Endothelial-to-Mesenchymal Transition: Unlocking New Therapeutic Avenues for Portal Vein Thrombosis in Cirrhosis

Highlight

Portal vein thrombosis (PVT) in cirrhosis involves unique structural and cellular changes, including eccentric intimal hyperplasia and extracellular matrix accumulation. The endothelial-to-mesenchymal transition (EndMT) pathway is upregulated in portal vein endothelial cells from patients with PVT, representing a novel pathophysiological mechanism. Statins, identified through transcriptomic and drug repurposing analyses, mitigate EndMT hallmarks in vitro, offering a new therapeutic avenue beyond conventional anticoagulation.

Study Background

Portal vein thrombosis is a common and clinically significant complication in patients with cirrhosis, contributing to worsened portal hypertension, liver decompensation, and impaired eligibility for transplantation. Despite the clinical burden, the precise pathophysiology of PVT in the cirrhotic portal venous system remains incompletely understood. Current management primarily relies on anticoagulation; however, unlike thromboses in other vascular beds, portal vein thrombi often resist full recanalization with anticoagulants alone, highlighting an urgent need for better mechanistic insight and alternative therapeutic strategies.

Emerging evidence suggests that vascular remodeling and endothelial dysfunction might underlie PVT pathogenesis in cirrhosis. Yet, the specific cellular mechanisms, including contributions from endothelial plasticity, remain unclear. This study aimed to characterize histological and molecular alterations in the portal venous vascular bed and identify targetable pathways to inform novel therapies.

Study Design

The investigators performed a comparative histological and molecular analysis using portal vein specimens from explanted livers of three groups: patients with cirrhosis and PVT, patients with cirrhosis without PVT, and healthy liver donors serving as controls. Specimens were assessed for structural changes, cellular composition, and extracellular matrix deposition.

Additionally, portal vein endothelial cells (PVECs) were isolated for transcriptomic profiling to identify differentially expressed pathways associated with PVT. In silico drug repurposing screened for candidate agents capable of reversing the observed molecular alterations. Finally, primary human PVECs were treated in vitro with statins to validate therapeutic efficacy against endothelial-to-mesenchymal transition.

Key Findings

Histopathological analyses revealed a pronounced eccentric thickening of the tunica intima in portal veins affected by thrombosis. This hyperplasia was characterized by accumulation of extracellular matrix components and increased cellularity comprising inflammatory and myofibroblast-like cells. These changes significantly narrowed the portal vein lumen, providing a plausible substrate for thrombosis formation.

Transcriptomic profiling identified the endothelial-to-mesenchymal transition (EndMT) pathway as markedly upregulated in PVECs from patients with PVT compared to those without thrombosis and controls. EndMT is a phenotypic shift where endothelial cells acquire mesenchymal and fibroblast-like properties, contributing to pathological vascular remodeling.

In silico drug repurposing implicated statins—a class of HMG-CoA reductase inhibitors widely used for hyperlipidemia—as potential agents targeting EndMT-related gene expression changes. When primary human PVECs were exposed to statins in vitro, hallmarks of EndMT including mesenchymal marker expression and extracellular matrix production were significantly attenuated.

The study thus delineates a link between maladaptive endothelial remodeling driven by EndMT and portal vein luminal narrowing that predisposes to thrombosis in cirrhosis. These insights illuminate EndMT as a novel mechanistic contributor to PVT and identify statins as promising therapeutics with dual vascular protective and antifibrotic effects.

Expert Commentary

This research advances our understanding of portal vein thrombosis beyond the traditional coagulation paradigm, emphasizing the importance of endothelial plasticity and vessel wall remodeling in cirrhosis. EndMT represents an emerging pathobiologic mechanism increasingly recognized in diverse vascular fibrotic diseases. Its implication in PVT underscores the complex interplay between inflammation, extracellular matrix dynamics, and endothelial phenotypic changes in portal hypertension complications.

Clinically, these findings may explain the limited success of anticoagulation alone in resolving portal vein thrombi, as luminal narrowing from intimal hyperplasia remains unaddressed. Targeting EndMT with statins, which are known to exert pleiotropic effects including endothelial stabilization, anti-inflammatory actions, and inhibition of fibroblast activation, offers a compelling adjunct or alternative strategy.

Nonetheless, the translational leap from in vitro attenuation of EndMT to clinical efficacy in PVT warrants further investigation. Future randomized trials are needed to assess appropriate statin dosing, timing, and safety in cirrhotic patients with established or impending PVT. Additional exploration into other modulators of EndMT could also expand therapeutic options.

Limitations of the study include the observational nature of histological findings and reliance on isolated PVEC cultures that may not fully recapitulate in vivo complexities. Furthermore, the heterogeneous etiology and severity of cirrhosis among patients might influence vascular remodeling patterns.

Conclusion

Portal vein thrombosis in cirrhosis is driven in part by endothelial-to-mesenchymal transition-mediated maladaptive vascular remodeling resulting in intimal hyperplasia and luminal narrowing. This novel mechanistic insight highlights EndMT as a promising target for intervention. Statins have demonstrated potential to mitigate EndMT in vitro, positioning them as attractive candidates for repurposing to improve PVT management.

These findings invite a paradigm shift in understanding and treating PVT, moving beyond anticoagulation to address vessel wall biology. Further clinical studies are essential to translate these molecular discoveries into effective therapies that reduce morbidity and mortality in patients with cirrhosis.

Funding and Clinical Trials

The study was supported by institutional and research grants, as detailed in the original publication. No clinical trial registration was reported for the in vitro component; prospective interventional studies will require formal registration.

References

Anton A, Shalaby S, Botero ML, Blasi A, Fundora Y, Barace S, Montañés R, García-Calderó H, Velasco-de Andrés M, Orts L, Madubashetha H, Montironi C, Olivas P, Crespo G, Bazán C, Zambrano-Huailla R, Aristu Zabalza P, Argemí J, Friedman SL, García-Pagán JC, Campreciós G, Hernández-Gea V. Endothelial-to-mesenchymal transition: A targetable mechanism that contributes to portal vein thrombosis in cirrhosis. Hepatology. 2026 Jul 1;84(1):91-105. doi: 10.1097/HEP.0000000000001547. Epub 2025 Oct 6. PMID: 41144554; PMCID: PMC13275091.

Anton A, Shalaby S, Botero ML, et al. Endothelial-to-mesenchymal transition: A targetable mechanism that contributes to portal vein thrombosis in cirrhosis. Hepatology. 2025;84(1):91-105. PMID: 41144554.