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

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 induced by CCl₄. Notch activation attenuated eNOS-sGC signaling, and activation of sGC by YC-1 reversed the dedifferentiation phenotype. In addition, Notch activation subverted the hepatocyte-supporting angiocrine profile of LSECs by downregulating critical hepatocyte mitogens including Wnt2a, Wnt9b, and HGF. This led to compromised hepatocyte proliferation under both quiescent and regenerating conditions. While the 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. CONCLUSIONS: Endothelial Notch activation results in LSEC dedifferentiation and accelerated liver fibrogenesis through the eNOS-sGC signaling, and alters the angiocrine profile of LSECs to compromise hepatocyte proliferation and liver regeneration. This article is protected by copyright. All rights reserved.

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