Hydrostatic pressure driven vascular degeneration in cirrhosis [pLSEC WT/KO]

The role of pathological vascular degeneration in cirrhosis remains poorly understood. In this study, we engineered multidimensional vascular models to replicate the pathological characteristics of liver sinusoidal endothelial cells (LSECs) at various fibrosis stages. Our investigation revealed that LSEC response to hydrostatic pressure is matrix stiffness-dependent, with LSECs survival when cultured on soft matrices, while those cultured on hard matrices experiencing cellular damage. The biomimic vascular in vitro model enabled us to identify GPR116 as a crucial membrane receptor of LSECs to sense and respond to hydrostatic pressure. GPR116 is specifically expressed in liver endothelial cells, and silencing GPR116 effectively protected the endothelial cells from hydrostatic pressure-induced damage on hard matrix, consequently inhibiting hepatic stellate cell activation and collagen remodeling. Thus, our findings highlight GPR116 as an indispensable pressure sensor in hepatic sinusoidal endothelium, playing a pivotal role in vascular remodeling during cirrhosis. Overall design: To investigate the role of GPR116 in vascular remodeling, we use conditional knockout mice (GPR116fl/fl Cdh5CreERT2) to selectively suppress GPR116 expression in endothelial cells. Subsequently, we induced liver fibrosis using CCl4 for 12 weeks to simulate late-stage fibrosis. We isolated primary LSEC from KO and WT mouse. Comparative gene expression profiling analysis of RNA-seq data for primary LSEC from KO and WT mouse.