Activation of the Integrin αV-YAP-CTGF Axis in Liver Sinusoidal Endothelial Cells Promotes Liver Fibrogenesis, Leading to Portal Hypertension and Liver Carcinogenesis in Congestive Hepatopathy

BACKGROUND & AIMS: Chronic liver congestion progresses to liver fibrosis, eventually leading to cirrhosis and cancer. This study aimed to elucidate the mechanism of congestive hepatopathy (CH), focusing on liver sinusoidal endothelial cells (LSECs). METHODS: Partial inferior vena cava ligation (pIVCL) was performed to induce hepatic congestion in mice. Single-cell RNA sequencing (scRNA-seq) was conducted on murine livers after pIVCL. Cells underwent hydrostatic pressure stimulation. scRNA-seq and spatial transcriptomics were performed on human livers from patients with Fontan-associated liver disease. RESULTS: The scRNA-seq analysis showed that the integrin signaling pathway and yes-associated protein (YAP) were activated in pericentral LSECs after pIVCL. The most upregulated gene in pericentral LSECs was connective tissue growth factor (CTGF). Hydrostatic pressure activated YAP through integrin αV, leading to the upregulation of CTGF and type IV collagen (COL4) expression in LSECs. LSEC-derived CTGF upregulated the type I collagen (COL1) and COL4 expression in hepatic stellate cells. CTGF knockout in endothelial cells ameliorated CH-induced liver fibrosis and portal hypertension and even suppressed liver tumorigenesis. Integrin αV inhibition alleviated CH-induced liver fibrosis and portal hypertension with the decreased expression of CTGF, COL4, and COL1. scRNA-seq and spatial transcriptomics of clinical Fontan-associated liver disease samples revealed YAP activation and CTGF upregulation in pericentral LSECs, potentially leading to increased COL4 expression in LSECs and increased COL1 expression in hepatic stellate cells as fibrosis progressed. CONCLUSIONS: CTGF induction in LSECs may play an upstream role in the fibrogenesis of CH. The integrin αV-YAP-CTGF axis in LSECs could be a potential therapeutic target for CH.