AUTHOR=Koch Philipp-Sebastian , Sandorski Kajetan , Heil Joschka , Schmid Christian D. , Kürschner Sina W. , Hoffmann Johannes , Winkler Manuel , Staniczek Theresa , de la Torre Carolina , Sticht Carsten , Schledzewski Kai , Taketo Makoto Mark , Trogisch Felix A. , Heineke Joerg , Géraud Cyrill , Goerdt Sergij , Olsavszky Victor 

TITLE=Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation

JOURNAL=Frontiers in Physiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.722394

DOI=10.3389/fphys.2021.722394

ISSN=1664-042X

ABSTRACT=<p>Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood–brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific <italic>Clec4g-iCre</italic> mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant <italic>Clec4g-iCre</italic><sup><italic>tg</italic>/<italic>wt</italic></sup><italic>;Ctnnb1(Ex3)</italic><sup><italic>fl</italic>/<italic>wt</italic></sup> (<italic>Ctnnb1</italic><sup><italic>OE</italic>−<italic>EC</italic></sup>) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation <italic>(CD)34</italic> and <italic>Apln</italic>. Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but <italic>Ctnnb1</italic><sup><italic>OE</italic>−<italic>EC</italic></sup> mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As <italic>Clec4g-iCre</italic> is active in a subset of cardiac ECs, it was not unexpected that <italic>Ctnnb1</italic><sup><italic>OE</italic>−<italic>EC</italic></sup> mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.</p>