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

Portal vein thrombosis (PVT) is a prevalent thrombotic complication in cirrhosis, yet its pathophysiology remains elusive, hindering effective treatment strategies. Unlike thrombosis in other vascular beds, anticoagulation often fails to achieve complete recanalization in PVT, highlighting the need of alternative therapeutic approaches. We investigated portal vein endothelium involvement in PVT pathogenesis, identifying potential therapeutic targets. We isolated for the first time primary human portal vein endothelial cells (PVEC) from explanted livers of cirrhotic patients with and without PVT, as well as from a control group without portal hypertension and conducted RNA sequencing. Transcriptomic analysis unveiled endothelial-to-mesenchymal transition (EndMT) pathway as a key mechanism underlying PVT in cirrhosis, predominantly induced through TGFß/SMAD mechanism. Remarkably, coagulation markers remained unaffected. In silico drug repurposing identified statins as potential agents targeting these alterations. Our study elucidates significant endothelial changes in the portal vein of cirrhotic patients, particularly pronounced in those with PVT, with EndMT emerging as a pivotal process. Simvastatin emerges as a promising therapeutic option for PVT treatment and prevention by modulating EndMT in PVEC. Overall design: To investigate the role of the portal vein endothelium in the pathogenesis of portal vein thrombosis (PVT) we isolated human portal vein endothelial cells (PVEC) from the explanted liver from patients with cirrhosis without and with PVT undoergoing liver transplantation (LT). As controls we used patients undergoing LT due to polychistosis, a condition without portal hypertension. We then expanded the obtained cells and performed bulk RNAseq with cells at passage 1. Comparative gene expression analysis was performed between control PVECs vs PVEC without PVT, and between PVEC without PVT and PVEC with PVT (CT-PVEC, CH-PVEC and PVT-PVEC).