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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.

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.

Fast locomotory muscles, which are responsible for generating the highest power outputs, are more vulnerable to aging than slow muscles. In this study, we aimed to evaluate the impact of middle age and voluntary physical activity on capillarization and angiogenic potential in fast locomotory muscles. Middle-aged (M-group) and young (Y-group) wild-type FVB female mice were randomly assigned to either the sedentary or trained group undergoing 8-week spontaneous wheel running (8-sWR). Capillary density (assessed via immunohistochemical capillary staining and Western immunoblotting) of the fast locomotory muscles in the M-group (15-months old) was not significantly different compared to the Y-group (4-months old). Nevertheless, the expression of key pro-angiogenic genes in the fast muscle of the M-group was lower than that in the fast muscle of Y-group. 8-sWR had no impact on muscle capillarization; however, it increased fast muscle Vegfa expression in both the M and Y groups. We concluded that although fast muscle capillarization is still preserved in middle age, nevertheless the angiogenic potential (at least at the level of gene expression) is significantly reduced at this stage of aging. Moderate-intensity voluntary physical activity had no effect on capillary density, but it increased the angiogenic potential of the fast muscle.

Background: Gandouling (GDL) is a compound prepared in Chinese medicine and demonstrates favorable clinical efficacy. Studies have shown that sinusoid capillarization promoted hepatic fibrosis and was a potential target for preventing and treating liver fibrosis in Wilson’s disease (WD). This study aimed to explore whether GDL inhibited the sinusoid capillarization in WD by blocking the communication between hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs). Methods: In this study, Atp7b-H1071Q (TX) mice were used as the WD model mice, and CuSO4⋅5H2O treated LX-2 cells were used as the HSC activation model. We used scanning electron microscopy, vascular tube formation assay, Western blot, cell transfection, and co-culture system to study how GDL blocked the communication between HSCs and LSECs, as well as its inhibitory effect on the sinusoid capillarization. Results: We found that GDL alleviated liver fibrosis in TX mice, inhibited HSC activation, and sinusoid capillarization in TX mice. Excessive secreted VEGFA by LX-2 cells promoted the sinusoid capillarization, played the role of a messenger molecule, and GDL blocked the VEGFA-mediated HSCs-LSECs communication. Furthermore, bioinformatics analysis, molecular docking, and molecular dynamics suggested that GDL may exert its effect by modulating the PDGFRβ/ERK/VEGFA signaling axis. We validated the above observation through experiments, that GDL reduced PDGFRβ/ERK signal pathway in LX-2 cells, inhibited the expression of messenger molecule VEGFA, blocked HSCs-LSECs communication, inhibited sinusoid capillarization, and improved WD. Conclusions: GDL blocked the communication between HSCs and LSECs and inhibited the sinusoid capillarization associated with liver fibrosis in WD by the PDGFRβ/ERK/VEGFA signaling axis.

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.

Silent information regulator sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase with potent anti-arterial aging activities. Its protective function in aging-related diseases has been extensively studied. In the microcirculation, SIRT1 plays a crucial role in preventing microcirculatory endothelial senescence by suppressing inflammation and oxidative stress while promoting mitochondrial function and optimizing autophagy. It suppresses hypoxia-inducible factor-1α (HIF-1α)-mediated pathological angiogenesis while promoting healthy, physiological capillarization. As a result, SIRT1 protects against microvascular dysfunction, such as diabetic microangiopathy, while enhancing exercise-induced skeletal muscle capillarization and energy metabolism. In the brain, SIRT1 upregulates tight junction proteins and strengthens their interactions, thus maintaining the integrity of the blood−brain barrier. The present review summarizes recent findings on the regulation of microvascular function by SIRT1, the underlying mechanisms, and various approaches to modulate SIRT1 activity in microcirculation. The importance of SIRT1 as a molecular target in aging-related diseases, such as diabetic retinopathy and stroke, is underscored, along with the need for more clinical evidence to support SIRT1 modulation in the microcirculation.

Liver sinusoidal endothelial cells (LSECs), with their unique morphology and function, have garnered increasing attention in chronic liver disease research. This review summarizes the critical roles of LSECs under physiological conditions and in two representative chronic liver diseases: metabolic dysfunction-associated steatotic liver disease (MASLD) and liver cancer. Under physiological conditions, LSECs act as selective barriers, regulating substance exchange and hepatic blood flow. Interestingly, LSECs exhibit contrasting roles at different stages of disease progression: in the early stages, they actively resist disease advancement and help restore sinusoidal homeostasis; whereas in later stages, they contribute to disease worsening. During this transition, LSECs undergo capillarization, lose their characteristic markers, and become dysfunctional. As the disease progresses, LSECs closely interact with hepatocytes, hepatic stellate cells, various immune cells, and tumor cells, driving processes such as steatosis, inflammation, fibrosis, angiogenesis, and carcinogenesis. Consequently, targeting LSECs represents a promising therapeutic strategy for chronic liver diseases. Relevant therapeutic targets and potential drugs are summarized in this review.

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.