肝窦毛细血管化和血管生成在逆转肝纤维化/肝硬化门脉高压症中起关键作用。前期研究发现，H2S是体内重要的血管生成抑制因子，Dll4-Notch信号在血管增生中发挥重要作用。肝硬化门脉高压患者肝组织表达Dll4，肝星状细胞（HSC）分泌H2S并调节肝窦内皮细胞（LSEC）的功能。因此，本项目拟阐明H2S及其前体药物通过Dll4-Notch信号在LSEC毛细血管化及新生血管的作用及其机制。通过HSC与LSEC混合培养并建立体外类器官（organoid），阐明H2S-Dll4对LSEC毛细血管化及新生血管形成的作用及其机制。通过四氯化碳（CCl4）腹腔注射建立肝窦毛细血管化小鼠动物模型，探讨H2S及其前体药物逆转肝硬化门脉高压症的潜在新靶点及其机制。从抑制血管生成及肝窦毛细血管化的新角度，阐明逆转肝纤维化及肝硬化门脉高压症的新靶点、潜在药物及其理论依据，具有重要的理论创新和应用前景。

Capillarization of liver sinusoidal endothelial cells (LSEC) and hepatic vascular remodeling play a key role in hepatic fibrosis, cirrhosis and portal hypertension. Two factors are crucial in regulating liver angiogenesis: H2S, the most important angiogenesis inhibitor in the body and the Dll4-Notch signaling that inhibits vascular proliferation. Own preliminary studies observed that (1) Sinusoidal Dll4 expression positively correlated with live fibrosis, however, significantly reduced in decompensated cirrhotic liver, and (2) hepatic stellate cells (HSC) secrete H2S and thus regulate function of sinusoidal endothelial cells (LSEC). This project aims to investigate whether and how Dll4-Notch signaling mediates H2S and its prodrugs in the regulation of LSEC capillarization and hepatic vascular remodeling in vitro, in animals and organoids based on isolated primary HSC and LSEC. Based on planned experiments, we try to explore novel anti-cirrhosis/portal hypertension approaches, focusing on Dll4-Notch-H2S axis.