Angiocrine signaling in the hepatic sinusoids in health and disease

Abstract

The capillary network irrigating the liver is important not only for nutrient and oxygen delivery, but also for the signals distributed to other hepatic cell types necessary to maintain liver homeostasis. During development, endothelial cells are a key component in liver zonation. In adulthood, they maintain hepatic stellate cells and hepatocytes in quiescence. Their importance in pathobiology is highlighted in liver regeneration and chronic liver diseases, where they coordinate paracrine cell behavior. During regeneration, liver sinusoidal endothelial cells induce hepatocyte proliferation and angiogenesis. During fibrogenesis, they undergo morphological and functional changes, which are reflected by their role in hepatic stellate cell activation, inflammation, and distorted sinusoidal structure. Therapeutic strategies to target angiocrine signaling are in progress but are in the early stages. Here, we offer a short synthesis of recent studies on angiocrine signaling in liver homeostasis, regeneration, and fibrogenesis.

Keywords: angiocrine signaling; angiogenesis; endothelial cell; fibrosis; liver regeneration.

Fig. 1.

Left: in hepatic health, liver sinusoidal endothelial cells (LSECs) keep hepatic stellate cells (HSCs) in quiescence. LSECs secrete large amounts of nitric oxide (NO) and small amounts of endothelin (ET)-1. NO contributes to HSC relaxation in basal conditions. LSECs also secrete a small amount of hepatocyte growth factor (HGF), which is not sufficient for hepatocyte proliferation. Despite multiple studies, the role of NO in HSC quiescence remains under investigation. Middle: during regeneration, LSECs play an important role. They induce hepatocyte proliferation by secreting large amounts of HGF and small quantities of angiopoietin 2 (Angpt2) and TGFβ during the early phase (phase I). Throughout the angiogenic phase (phase II), LSECs increase their Angpt2 and TGFβ secretion, which, in an autocrine manner, induces their growth. Hepatocytes secrete VEGF, which is crucial during angiogenesis. LSECs can also lead to platelet infiltration. Right: in liver fibrosis, LSECs undergo defenestration. They increase ET-1 secretion and decrease NO release, which leads to HSC contraction. LSECs attract HSCs by secreting a large amount of stromal cell-derived factor (SDF-1) and induce HSC migration through the release of sphingosine kinase inhibitor (SK1)-containing exosomes (small red spheres). HSCs produce large amounts of collagen and reciprocally increase their VEGF secretion, leading to angiogenesis. LSECs also play a role in hepatic inflammation by interacting with monocytes/macrophages and neutrophils. BMP2, bone morphogenetic protein 2; MF, myofibroblasts; PDGF-C, platelet-derived growth factor C. (The Servier Medical Art image bank was used to prepare this figure.)