Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice

Hepatology. 2018 Aug;68(2):677-690. doi: 10.1002/hep.29834. Epub 2018 Apr 26.

Abstract

Liver sinusoidal endothelial cells (LSECs) critically regulate liver homeostasis and diseases through angiocrine factors. Notch is critical in endothelial cells (ECs). In the current study, Notch signaling was activated by inducible EC-specific expression of the Notch intracellular domain (NIC). We found that endothelial Notch activation damaged liver homeostasis. Notch activation resulted in decreased fenestration and increased basement membrane, and a gene expression profile with decreased LSEC-associated genes and increased continuous EC-associated genes, suggesting LSEC dedifferentiation. Consistently, endothelial Notch activation enhanced hepatic fibrosis (HF) induced by CCl4 . Notch activation attenuated endothelial nitric oxide synthase (eNOS)/soluble guanylate cyclase (sGC) signaling, and activation of sGC by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) reversed the dedifferentiation phenotype. In addition, Notch activation subverted the hepatocyte-supporting angiocrine profile of LSECs by down-regulating critical hepatocyte mitogens, including Wnt2a, Wnt9b, and hepatocyte growth factor (HGF). This led to compromised hepatocyte proliferation under both quiescent and regenerating conditions. Whereas expression of Wnt2a and Wnt9b was dependent on eNOS-sGC signaling, HGF expression was not rescued by the sGC activator, suggesting heterogeneous mechanisms of LSECs to maintain hepatocyte homeostasis.

Conclusion: Endothelial Notch activation results in LSEC dedifferentiation and accelerated liver fibrogenesis through eNOS-sGC signaling, and alters the angiocrine profile of LSECs to compromise hepatocyte proliferation and liver regeneration (LR). (Hepatology 2018).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Culture Techniques
  • Cell Proliferation
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Profiling
  • Hepatocytes / metabolism*
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / metabolism*
  • Liver Regeneration / genetics*
  • Liver Regeneration / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Real-Time Polymerase Chain Reaction
  • Receptors, Notch / metabolism*
  • Signal Transduction / genetics

Substances

  • Receptors, Notch