Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.

Portal vein thrombosis (PVT) is a common complication among patients with cirrhosis. However, its pathophysiology is not well established and there are currently very few predictive factors, none of which are actually useful, from a clinical perspective. The contribution of each of the vertices of Virchow’s triad, e.g., blood hypercoagulability, blood flow, and portal vein endothelial damage in the development of PVT is not clear. In this review, we aim to recapitulate the latest studies on the field of PVT development in order to understand its mechanisms and discuss some of the future directions in the study of this important complication of cirrhosis.

Chronic liver diseases are multifactorial and the need to develop effective therapies is high. Recent studies have shown the potential of ameliorating liver disease progression through protection of the liver endothelium. Polyamine spermidine (SPD) is a caloric restriction mimetic with autophagy-enhancing properties capable of prolonging lifespan and with a proven beneficial effect in cardiovascular disease in mice and humans. We evaluated the use of dietary supplementation with SPD in two models of liver disease (CCl₄ and CDAAH diet). We analyzed the effect of SPD on endothelial dysfunction in vitro and in vivo. C57BL/6J mice were supplemented with SPD in the drinking water prior and concomitantly with CCl₄ and CDAAH treatments. Endothelial autophagy deficient (Atg7endo) mice were also evaluated. Liver tissue was used to evaluate the impact of SPD prophylaxis on liver damage, endothelial dysfunction, oxidative stress, mitochondrial status, inflammation and liver fibrosis. SPD improved the endothelial response to oxidative injury in vitro and improved the liver endothelial phenotype and protected against liver injury in vivo. SPD reduced the overall liver oxidative stress and improved mitochondrial fitness. The absence of benefits in the Atg7endo mice suggests an autophagy-dependent effect of SPD. This study suggests SPD diet supplementation in early phases of disease protects the liver endothelium from oxidative stress and may be an attractive approach to modify the chronic liver disease course and halt fibrosis progression.

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.

Background: Porto‐sinusoidal vascular disorder (PSVD) involves a group of rare vascular liver diseases of unknown aetiology that may lead to the development of portal hypertension and its life‐threatening complications. Its pathophysiology is not well understood, and animal models described to date do not fully recapitulate human disease.Methods: We developed three different PSVD rat models by either immunosensitization (repetitive intraportal LPS or intramuscular spleen extract injections) or toxic (Selfox: combination of FOLFOX and a selenium‐enriched diet) treatment and characterized them at haemodynamic, histological, biochemical and transcriptional levels. We compared these results to human data.Results: All three models developed significant portal hypertension, while only the LPS and the Selfox models displayed PSVD‐specific and nonspecific histological alterations in the absence of cirrhosis. Transcriptional comparison between rat models and human data showed that both LPS and Selfox models recapitulate the main transcriptional alterations observed in humans, especially regarding haemostasis, oxidative phosphorylation and cell cycle regulation. Reproducibility and feasibility was higher for the Selfox model.Conclusions: The Selfox rat model faithfully reproduces the main alterations described in PSVD. Its use as a preclinical model for drug testing in progressing PSVD can be a significant step forward towards the development of new therapeutic targets for this rare condition.