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Sinusoidal capillarization – key symptoms of liver fibrosis progression – represents potential therapeutic targets. tRNA modification‐mediated tRNA‐derived small RNAs (tsRNAs) play a role in angiogenesis. NSun2, an RNA methyltransferase, generates a significant number of tsRNAs. However, the role of NSun2 and its mediated tsRNAs in liver fibrosis remains unclear. In this study, NSun2 deficiency was found to inhibit sinusoidal capillarization, alleviating liver fibrosis. Furthermore, endothelial cell angiogenesis and migration were disrupted in NSun2 knockout mice. Mechanistically, reduced NSun2 expression led to alterations in the functional tsRNAs tRF‐1‐S25 and tRF‐5‐V31, which regulate sinusoidal capillarization by targeting key proteins, including DUSP1 and FAK – crucial clinical targets. Moreover, intravenous injection of tRF‐1‐S25 and tRF‐5‐V31 inhibitor rescued liver fibrosis in mice. In conclusion, tsRNAs generated by NSun2‐mediated modification of tRNAs inhibit sinusoidal capillarization. Furthermore, targeting the DUSP1/FAK/p‐FAK pathway offers an innovative approach to treat this disease. NSun2 deficiency inhibited sinusoidal capillarization, alleviating liver fibrosis. Reduced NSun2 expression led to alterations in the functional tsRNAs tRF‐1‐S25 and tRF‐5‐V31, which regulate sinusoidal capillarization by targeting key proteins, including DUSP1 and FAK – crucial clinical targets – offering a novel RNA‐based therapeutic approach for liver fibrosis.

Cirrhotic portal hypertension, the most prevalent and clinically significant complication of liver cirrhosis, manifests as elevated portal venous pressure and is associated with severe complications. Although much research on the mechanisms of portal hypertension has focused on liver fibrosis, less attention has been given to the role of intrahepatic and extrahepatic vascular dysfunction, particularly with respect to extrahepatic vasculature. While the role of hepatic fibrosis in cirrhotic portal hypertension is undeniable, the underlying mechanisms involving intrahepatic and extrahepatic vasculature are highly complex. Sinusoidal capillarization and endothelial dysfunction contribute to increased intrahepatic vascular resistance. Hemodynamic changes in the extrahepatic circulation, including splanchnic vasodilation and hyperdynamic circulation, play a significant role in the development of portal hypertension. Additionally, therapeutic strategies targeting these vascular mechanisms are diverse, including improvement of sinusoidal microcirculation, therapies targeting hepatic stellate cells activation, and pharmacological modulation of systemic vascular tone. Therefore, in this review, we will discuss the vascular-related mechanisms and treatment progress of portal hypertension in cirrhosis to provide a new theoretical basis and practical guidance for clinical treatment.

Sinusoidal obstruction syndrome (SOS) is a type of fatal hepatic injury, which predominantly occurs following exposure to drugs, such as oxaliplatin, or bone marrow transplantation. Extravasated platelet aggregation (EPA) plays an important role in the development of SOS in rat and mouse models. Furthermore, platelets invading the space of Disse adhere to hepatocytes and are phagocytized in patients with SOS. Aging platelets and platelets in patients with sepsis are phagocytized by hepatocytes through Ashwell-Morell receptors, and thrombopoietin (TPO) is produced by the JAK2-STAT3 signaling pathway. The purpose of the present study was to examine the significance of TPO as a biomarker of SOS. SOS was induced in Crl:CD1(ICR) female mice by intraperitoneal administration of monocrotaline (MCT). TPO levels were measured in the serum and liver tissue. Pathological and immunohistochemical studies of the liver were performed to analyze the expression levels of TPO. TPO mRNA expression levels were measured using reverse transcription-quantitative PCR. In the SOS model, the platelet counts in peripheral blood samples were significantly decreased at 24 and 48 h after MCT treatment as compared with that at 0 h. In addition, a pathological change in hepatic zone 3 was observed in the SOS model group. Furthermore, the protein levels of TPO in liver tissue were significantly increased in the SOS model group compared with those in the control group, which was confirmed by immunohistochemistry. By contrast, serum TPO protein levels were significantly decreased in the SOS model group compared with those in the control group. These results indicated that EPA may induce sinusoidal endothelial fenestration in a mouse model of SOS, preventing TPO from translocating into the blood. In conclusion, serum TPO levels may be reduced in a mouse model of SOS owing to the accumulation in hepatocytes, suggesting that TPO could be a useful biomarker of SOS.

Among the various consequence arising from lung injury, hepatic fibrosis is the most severe. Decreasing the effects of hepatic fibrosis remains one of the primary therapeutic challenges in hepatology. Dysfunction of hepatic sinusoidal endothelial cells is considered to be one of the initial events that occur in liver injury. Vascular endothelial growth factor signaling is involved in the progression of genotype changes. The aim of the present study was to determine the effect of the tyrosine kinase inhibitor, vatalanib, on hepatic fibrosis and hepatic sinusoidal capillarization in a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis. Liver fibrosis was induced in BALB/c mice using CCl4 by intraperitoneal injection for 6 weeks. The four experimental groups included a control, and three experimental groups involving administration of CCl4, vatalanib and a combination of the two. Histopathological staining and measuring live hydroxyproline content evaluated the extent of liver fibrosis. The expression of α-smooth muscle actin (SMA) and cluster of differentiation (CD) 34 was detected by immunohistochemistry. Collagen type I, α-SMA, transforming growth factor (TGF)-β1 and vascular endothelial growth factor receptor (VEGFR) expression levels were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The average number of fenestrae per hepatic sinusoid was determined using transmission electron microscopy. Liver fibrosis scores and hydroxyproline content were decreased in both vatalanib groups. In addition, both doses of vatalanib decreased mRNA expression levels of hepatic α-SMA, TGF-β1, collagen-1, VEGFR1, and VEGFR2. Levels of α-SMA and CD34 protein were decreased in the vatalanib group compared with the CCl4 group. There were significant differences in the number of fenestrae per sinusoid between the groups. The present study identified that administration of vatalanib was associated with decreased liver fibrosis and hepatic sinusoidal capillarization in CCl4-induced mouse models, and is a potential compound for counteracting liver fibrosis.

The aim of the present study was to detect the effect of the recombinant human endostatin Endostar on hepatic sinusoidal capillarization in CCl4-induced murine models of liver fibrosis. The liver fibrosis model was induced in BALB/c mice using intraperitoneal injection of CCl4 for 6 weeks. Animals were divided into the following six treatment groups: Group 1, normal animals; group 2, CCl4-induced liver fibrosis; group 3, CCl4+Endostar 20 mg/kg/day for 6 weeks; group 4, CCl4+Endostar 10 mg/kg/day for 6 weeks; group 5, CCl4+Endostar 20 mg/kg/day for 4 weeks; and group 6, CCl4+Endostar 10 mg/kg/day for 4 weeks. The average number of fenestrae per hepatic sinusoid was determined using transmission electron microscopy. Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) 1 and 2 expression was detected by western blot analysis. There were significant differences in the number of fenestrae per sinusoid between the normal control and untreated model fibrotic mice (P<0.01), and between the untreated model and Endostar-treated mice (P<0.05). Endostar treatment was associated with reduced levels of VEGFR1 and VEGFR2 in liver tissues (P<0.01), as well as with decreased hepatic sinusoidal endothelial cell capillarization in CCl4-induced mouse models of liver fibrosis, and this effect may involve the VEGF pathway. However, further studies are required to confirm its involvement in other causes of liver fibrosis.

Unlike normal liver with the sinusoids, hepatocellular carcinomas (HCCs) possess capillaries. Whether these capillaries derive from the sinusoids remains unclear in human HCCs. This study aimed to examine sinusoidal capillarization in human HCCs and its relationship to the tumor size, arterialization and dedifferentiation. Thirty‐eight HCCs with a diameter of 10–140 mm were pathologically and angiographically examined. By electron microscopy, the microvasculature of tumors was classified into sinusoidal, intermediate and capillary types, which were all negative, partially positive and all positive, respectively, for four parameters, i.e., endothelial defenestration, continuous basement membrane, lack of Kupffer cells, and lack of lipid‐containing hepatic stellate cells. Well‐, moderately and poorly differentiated HCCs displayed sinusoidal/intermediate/capillary types, intermediate/capillary types and only capillary type, respectively, suggesting the transition from the sinusoids to capillaries in well‐differentiated (and probably moderately differentiated) HCCs. Furthermore, well‐differentiated HCCs with a diameter of less than 30 mm often received preferential portal venous blood, while moderately and poorly differentiated ones were all supplied with arterial blood, indicating a relationship between dedifferentiation and arterialization. In contrast, the microvascular type displayed no significant relationship with tumor size or arterialization in well‐differentiated HCCs. The present study has demonstrated that sinusoidal capillarization occurs in human well‐differentiated HCCs and seems to be related to dedifferentiation of parenchymal tumor cells, but not to tumor size or arterialization.

Liver sinusoidal endothelial cells (LSECs) are liver-specific endothelial cells with the highest permeability than other mammalian endothelial cells, characterized by the presence of fenestrae on their surface, the absence of diaphragms and the lack of basement membrane. Located at the interface between blood and other liver cell types, LSECs mediate the exchange of substances between the blood and the Disse space, playing a crucial role in maintaining substance circulation and homeostasis of multicellular communication. As the initial responders to chronic liver injury, the abnormal LSEC activation not only changes their own physicochemical properties but also interrupts their communication with hepatic stellate cells and hepatocytes, which collectively aggravates the process of liver fibrosis. In this review, we have comprehensively updated the various pathways by which LSECs were involved in the initiation and aggravation of liver fibrosis, including but not limited to cellular phenotypic change, the induction of capillarization, decreased permeability and regulation of intercellular communications. Additionally, the intervention effects and latest regulatory mechanisms of anti-fibrotic drugs involved in each aspect have been summarized and discussed systematically. As we studied deeper into unraveling the intricate role of LSECs in the pathophysiology of liver fibrosis, we unveil a promising horizon that pave the way for enhanced patient outcomes.

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. It is a critical pre-stage condition of severe hepatopathy, characterized by excessive accumulation of extracellular matrix components and ongoing chronic inflammation. To date, early prevention of liver fibrosis remains challenging. As the most abundant non-parenchymal hepatic cell population, liver sinusoidal endothelial cells (LSECs) are stabilizers that maintain the intrahepatic environment. Notably, LSECs dysfunction appears to be implicated in the progression of liver fibrosis via numerous mechanisms. Following sustained liver injury, they lose their fenestrae (cytoplasmic pores) and change their crosstalk with other cellular interactions in the hepatic blood environment. LSEC-targeted therapy has shown promising effects on fibrosis resolution, opening up new opportunities for anti-fibrotic therapy. In light of this, the present study summarized changes in LSECs during liver fibrosis and their interactions with hepatic milieu, as well as possible therapeutic approaches that specially target LSECs.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future.

Nonalcoholic fatty liver disease (NAFLD), especially its advanced stage nonalcoholic steatohepatitis (NASH), has become a threatened public health problem worldwide. However, no specific drug has been approved for clinical use to treat patients with NASH, though there are many promising candidates against NAFLD in the drug development pipeline. Recently, accumulated evidence showed that liver sinusoidal endothelial cells (LSECs) play an essential role in the occurrence and development of liver inflammation in patients with NAFLD. LSECs, as highly specialized endothelial cells with unique structure and anatomical location, contribute to the maintenance of liver homeostasis and could be a promising therapeutic target to control liver inflammation of NAFLD. In this review, we outline the pathophysiological roles of LSECs related to inflammation of NAFLD, highlight the pro-inflammatory and anti-inflammatory effects of LSECs, and discuss the potential drug development strategies against NAFLD based on targeting to LSECs.