Abstract | BACKGROUND AND AIMS: APPROACH AND RESULTS: Liver sinusoidal endothelial cell (LSEC)-selective Cre deleter line, Stab2-iCreF3 , was crossed with Acvrl1 -floxed mice to generate LSEC-specific Acvrl1 -deficient mice ( Alk1HEC-KO ). Alk1HEC-KO mice revealed hepatic vascular malformations and increased posthepatic flow, causing right ventricular volume overload. Transcriptomic analyses demonstrated induction of proangiogenic/tip cell gene sets and arterialization of hepatic vessels at the expense of LSEC and central venous identities. Loss of LSEC angiokines Wnt2 , Wnt9b , and R-spondin-3 ( Rspo3 ) led to disruption of metabolic liver zonation in Alk1HEC-KO mice and in liver specimens of patients with HHT. Furthermore, prion-like protein doppel ( Prnd ) and placental growth factor ( Pgf ) were upregulated in Alk1HEC-KO hepatic endothelial cells, representing candidates driving the organ-specific pathogenesis of HHT. In LSEC in vitro , stimulation or inhibition of ALK1 signaling counter-regulated Inhibitors of DNA binding (ID)1-3, known Alk1 transcriptional targets. Stimulation of ALK1 signaling and inhibition of ID1-3 function confirmed regulation of Wnt2 and Rspo3 by the BMP9/ALK1/ID axis. CONCLUSIONS: Hepatic endothelial ALK1 signaling protects from development of vascular malformations preserving organ-specific endothelial differentiation and angiocrine signaling. The long-term surviving Alk1HEC-KO HHT model offers opportunities to develop targeted therapies for this severe disease.
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Authors | Christian David Schmid, Victor Olsavszky, Manuel Reinhart, Vanessa Weyer, Felix A Trogisch, Carsten Sticht, Manuel Winkler, Sina W Kürschner, Johannes Hoffmann, Roxana Ola, Theresa Staniczek, Joerg Heineke, Beate K Straub, Jens Mittler, Kai Schledzewski, Peter Ten Dijke, Karsten Richter, Steven Dooley, Cyrill Géraud, Sergij Goerdt, Philipp-Sebastian Koch |
Journal | Hepatology (Baltimore, Md.)
(Hepatology)
Vol. 77
Issue 4
Pg. 1211-1227
(04 01 2023)
ISSN: 1527-3350 [Electronic] United States |
PMID | 35776660
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. |
Chemical References |
- Placenta Growth Factor
- Growth Differentiation Factor 2
- Stab2 protein, mouse
- Cell Adhesion Molecules, Neuronal
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Topics |
- Mice
- Female
- Animals
- Telangiectasia, Hereditary Hemorrhagic
(genetics)
- Endothelial Cells
(metabolism)
- Placenta Growth Factor
(metabolism)
- Liver
(pathology)
- Signal Transduction
- Growth Differentiation Factor 2
(metabolism)
- Cell Adhesion Molecules, Neuronal
(metabolism)
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