Endothelial-to-mesenchymal transition: A targetable mechanism that contributes to portal vein thrombosis in cirrhosis

Background and Aims: Portal vein thrombosis (PVT) is a frequent complication of cirrhosis, yet its pathophysiology remains elusive. Unlike thrombosis in other vascular beds, anticoagulation often fails to completely recanalize PVT, highlighting the need for greater mechanistic insight and alternative therapeutic approaches. Our study aimed to characterize the structural and cellular changes in the portal venous vascular bed to identify novel physiologically driven therapeutic targets. Approach and Results: Portal vein tissue specimens from explanted livers of patients with cirrhosis with and without PVT and from liver donors were histologically analyzed. PVT is associated with a remarkable eccentric thickening of the tunica intima due to accumulation of extracellular material and tunica intima increased cellularity. Transcriptomic analysis of human portal vein endothelial cells (PVEC) from patients with PVT identified the endothelial-to-mesenchymal transition (EndMT) pathway upregulated in PVECs from patients with PVT. In silico drug repurposing analysis identified statins as potential agents targeting these alterations. In vitro treatment with statins attenuated hallmarks of EndMT in primary human PVECs. Conclusions: In cirrhosis, the portal vein endothelium undergoes maladaptive remodeling marked by eccentric intimal hyperplasia, driven by ECM accumulation and infiltration of inflammatory and myofibroblast-like cells. This process narrows the lumen and may promote PVT. EndMT plays a key role in this transformation and emerges as a novel and promising therapeutic target. Notably, statins can attenuate EndMT, highlighting its potential in PVT treatment.