Cellular and molecular gastroenterology and hepatology · 2026
Notch signaling in the hepatic endothelial regulome mediates a dual reaction pattern of liver fibrosis and angiodysplasia.
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Schmid Christian D, Tuo Yang, Kürschner-Zacharias Sina W, Greco Alessandro, Schüler Julia, Hoffmann Johannes, Hardt Marius Roland, Trogisch Felix A, Weyer Vanessa, Sticht Carsten, Dooley Steven, Reiners-Koch Philipp-Sebastian, Olsavszky Victor, Goerdt Sergij, Winkler Manuel
Аннотация
BACKGROUND & AIMS: Unbalanced Notch signaling in liver sinusoidal endothelial cells (LSEC) leads either to vascular malformations or MASH-like liver fibrosis. Here, we investigated this dual reaction pattern for interactions of Notch signaling with Alk1 and Gata4 pathways which we hypothesized to contribute to aberrant angiogenesis or to liver fibrosis, respectively.
METHODS: Liver tissue of Clec4g-Cre/Rosa26N1ICD-IRES-GFP (NICDLSEC-OE) mice was studied by computed tomography, ultrasound, and (immuno)-histology. Pathway analysis was performed using RNA-seq, ATAC-seq or scRNA-seq data from LSEC of NICDLSEC-OE, Gata4-deficient (Gata4LSEC-KO), Alk1-deficient (Alk1LSEC-KO), or CDAA-fed mice.
RESULTS: NICDLSEC-OE mice showed simultaneous development of angiodysplasia and perisinusoidal liver fibrosis with loss of LSEC identity and stellate cell (HSC) activation. Transcriptome analysis revealed a stronger overlap of NICDLSEC-OE LSEC with Gata4LSEC-KO than Alk1LSEC-KO LSEC. Similarly, TOBIAS footprint analyses of NICDLSEC-OE LSEC showed major downregulation of GATA4 DNA binding, while DNA binding of Alk1-associated transcription factors remained unchanged. Correspondingly, angiocrine factors Vwf driving liver fibrosis and Efnb2 supporting arterial angiogenesis were up-regulated in NICDLSEC-OE and Gata4LSEC-KO LSEC, but not in Alk1LSEC-KO LSEC in vivo. Notch activation of LSEC in vitro induced VWF and EFNB2 expression, but down-regulation of ALK1-target gene ID1. In turn, EFNB2 induced up-regulation of proangiogenic genes VEGFR3 and RGCC in LSEC. In addition, short-term diet-induced MASH aggravated liver fibrosis in NICDLSEC-OE mice by largely Notch-independent pathogenic LSEC programs.
CONCLUSIONS: Notch-overactivated LSEC drive liver fibrosis via Gata4 loss, while they promote angiodysplasia largely independent of Alk1 signaling. Preventing pathogenic angiogenesis and liver fibrosis requires understanding the complex interactions within the LSEC regulome and the hepatic vascular niche.
METHODS: Liver tissue of Clec4g-Cre/Rosa26N1ICD-IRES-GFP (NICDLSEC-OE) mice was studied by computed tomography, ultrasound, and (immuno)-histology. Pathway analysis was performed using RNA-seq, ATAC-seq or scRNA-seq data from LSEC of NICDLSEC-OE, Gata4-deficient (Gata4LSEC-KO), Alk1-deficient (Alk1LSEC-KO), or CDAA-fed mice.
RESULTS: NICDLSEC-OE mice showed simultaneous development of angiodysplasia and perisinusoidal liver fibrosis with loss of LSEC identity and stellate cell (HSC) activation. Transcriptome analysis revealed a stronger overlap of NICDLSEC-OE LSEC with Gata4LSEC-KO than Alk1LSEC-KO LSEC. Similarly, TOBIAS footprint analyses of NICDLSEC-OE LSEC showed major downregulation of GATA4 DNA binding, while DNA binding of Alk1-associated transcription factors remained unchanged. Correspondingly, angiocrine factors Vwf driving liver fibrosis and Efnb2 supporting arterial angiogenesis were up-regulated in NICDLSEC-OE and Gata4LSEC-KO LSEC, but not in Alk1LSEC-KO LSEC in vivo. Notch activation of LSEC in vitro induced VWF and EFNB2 expression, but down-regulation of ALK1-target gene ID1. In turn, EFNB2 induced up-regulation of proangiogenic genes VEGFR3 and RGCC in LSEC. In addition, short-term diet-induced MASH aggravated liver fibrosis in NICDLSEC-OE mice by largely Notch-independent pathogenic LSEC programs.
CONCLUSIONS: Notch-overactivated LSEC drive liver fibrosis via Gata4 loss, while they promote angiodysplasia largely independent of Alk1 signaling. Preventing pathogenic angiogenesis and liver fibrosis requires understanding the complex interactions within the LSEC regulome and the hepatic vascular niche.