Liver sinusoidal endothelial cells contribute to portal hypertension through collagen type IV–driven sinusoidal remodeling

• DOI: 10.1172/jci.insight.174775
• Publication Date: 2024-05-07T16:01:07Z
• Authors: Can Gan; Usman Yaqoob; Jianwen Lu; Man Xie; Abid Anwar; Nidhi Jalan-Sakrikar; Sofia Jerez; Tejasav S. Sehrawat; Amaia Navarro-Cor...; Enis Kostallari; Nawras W. Habash; Sheng Cao; Vijay H. Shah
• Keywords: Sinusoid; Portal circulation

Portal hypertension (PHTN) is a severe complication of liver cirrhosis and associated with intrahepatic sinusoidal remodeling induced by resistance angiogenesis. Collagen type IV (COL4), major component basement membrane, forms in sinusoids upon chronic injury. However, the role, cellular source, expression regulation COL4 diseases are unknown. Here, we examined how produced it regulates fibrosis PHTN. Human cirrhotic sample RNA sequencing showed increased expression, which was further verified via immunofluorescence staining. Single-cell identified endothelial cells (LSECs) as predominant source upregulation mouse fibrotic liver. In addition, upregulated TNF-α/NF-κB-dependent manner through an epigenetic mechanism LSECs vitro. Indeed, utilizing CRISPRi-dCas9-KRAB epigenome-editing approach, repression enhancer-promoter interaction silencing gene expression. LSEC-specific mutation or vivo abrogated angiogenesis, thereby alleviated Our findings reveal that promote PHTN during deposition.