Endothelial Zeb2 preserves the hepatic angioarchitecture and protects against liver fibrosis

Author:

de Haan Willeke1ORCID,Dheedene Wouter1,Apelt Katerina2ORCID,Décombas-Deschamps Sofiane3ORCID,Vinckier Stefan45,Verhulst Stefaan6ORCID,Conidi Andrea7ORCID,Deffieux Thomas3,Staring Michael W1,Vandervoort Petra1,Caluwé Ellen1,Lox Marleen1,Mannaerts Inge6ORCID,Takagi Tsuyoshi8,Jaekers Joris9ORCID,Berx Geert1011ORCID,Haigh Jody1213,Topal Baki9ORCID,Zwijsen An1ORCID,Higashi Yujiro8ORCID,van Grunsven Leo A6ORCID,van IJcken Wilfred F J714,Mulugeta Eskeatnaf7ORCID,Tanter Mickael3,Lebrin Franck P G23,Huylebroeck Danny715ORCID,Luttun Aernout1ORCID

Affiliation:

1. Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Campus Gasthuisberg, Onderwijs & Navorsing 1, Herestraat 49, Box 911, 3000 Leuven, Belgium

2. Department of Internal Medicine (Nephrology), Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

3. Physics for Medicine Paris, Inserm, CNRS, ESPCI Paris, Paris Sciences et Lettres University, Paris, France

4. Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Leuven, Belgium

5. Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium

6. Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussels, Belgium

7. Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands

8. Department of Disease Model, Institute of Developmental Research, Aichi Developmental Disability Center, Aichi, Japan

9. Abdominal Surgery, UZ Leuven, Leuven, Belgium

10. Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

11. Cancer Research Institute Ghent (CRIG), Ghent, Belgium

12. Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

13. Research Institute in Oncology and Hematology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada

14. Center for Biomics-Genomics, Erasmus University Medical Center, Rotterdam, The Netherlands

15. Department of Development and Regeneration, KU Leuven, Leuven, Belgium

Abstract

Abstract Aims Hepatic capillaries are lined with specialized liver sinusoidal endothelial cells (LSECs) which support macromolecule passage to hepatocytes and prevent fibrosis by keeping hepatic stellate cells (HSCs) quiescent. LSEC specialization is co-determined by transcription factors. The zinc-finger E-box-binding homeobox (Zeb)2 transcription factor is enriched in LSECs. Here, we aimed to elucidate the endothelium-specific role of Zeb2 during maintenance of the liver and in liver fibrosis. Methods and results To study the role of Zeb2 in liver endothelium we generated EC-specific Zeb2 knock-out (ECKO) mice. Sequencing of liver EC RNA revealed that deficiency of Zeb2 results in prominent expression changes in angiogenesis-related genes. Accordingly, the vascular area was expanded and the presence of pillars inside ECKO liver vessels indicated that this was likely due to increased intussusceptive angiogenesis. LSEC marker expression was not profoundly affected and fenestrations were preserved upon Zeb2 deficiency. However, an increase in continuous EC markers suggested that Zeb2-deficient LSECs are more prone to dedifferentiation, a process called ‘capillarization’. Changes in the endothelial expression of ligands that may be involved in HSC quiescence together with significant changes in the expression profile of HSCs showed that Zeb2 regulates LSEC–HSC communication and HSC activation. Accordingly, upon exposure to the hepatotoxin carbon tetrachloride (CCl4), livers of ECKO mice showed increased capillarization, HSC activation, and fibrosis compared to livers from wild-type littermates. The vascular maintenance and anti-fibrotic role of endothelial Zeb2 was confirmed in mice with EC-specific overexpression of Zeb2, as the latter resulted in reduced vascularity and attenuated CCl4-induced liver fibrosis. Conclusion Endothelial Zeb2 preserves liver angioarchitecture and protects against liver fibrosis. Zeb2 and Zeb2-dependent genes in liver ECs may be exploited to design novel therapeutic strategies to attenuate hepatic fibrosis.

Funder

KU Leuven

Program Financing

European Research Council

Cosmetics Europe/European Commission FP7

Interuniversity Attraction Poles

Fonds voor Wetenschappelijk Onderzoek [FWO]

ZONMW OffRoad program

Marie Sklodowska-Curie Actions post-doctoral fellowship

Horizon 2020 Marie Skłodowska-Curie Actions-Innovative Training Network

FWO fellowship

Inserm Technology Research Accelerator grant in Biomedical Ultrasound

Dutch Cancer Society

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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