Hydrostatic pressure driven vascular degeneration in cirrhosis [4H24H]

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 how liver blood vessels respond to hydrostatic pressure stimulation, we collected cells cultured in 2D vessels on a substrate with a stiffness of 11 kPa. Transcriptome sequencing of LSECs exposed to pressure stimulation at 20mmHg for 0 hours, 4 hours, and 24 hours were conducted respectively in order to identify membrane-integrated proteins as potential mechanosensors.