University of Oulu

Frye, M., Stritt, S., Ortsäter, H., Hernandez Vasquez, M., Kaakinen, M., Vicente, A., Wiseman, J., Eklund, L., Martínez-Torrecuadrada, J., Vestweber, D., Mäkinen, T. (2020) EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity. eLife, 9, e57732. doi:10.7554/eLife.57732

EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity

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Author: Frye, Maike1,2; Stritt, Simon1; Ortsärter, Henrik1;
Organizations: 1Uppsala University, Department of Immunology, Genetics and Pathology, Uppsala, Sweden
2University Medical Center Hamburg-Eppendorf, Institute of Clinical Chemistry and Laboratory Medicine, Hamburg, Germany
3Biocenter Oulu, University of Oulu, Oulu, Finland
4Lymphatic Development Laboratory, Cancer Research UK London Research Institute, London, United Kingdom
5Discovery Biology, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
6Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
7Crystallography and Protein Engineering Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
8Max Planck Institute for Molecular Biomedicine, Mu ̈nster, Germany
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 8.7 MB)
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Language: English
Published: eLife Sciences Publications, 2020
Publish Date: 2020-12-04


Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. Here, we identified the transmembrane ligand EphrinB2 and its receptor EphB4 as critical homeostatic regulators of collecting lymphatic vessel integrity. Conditional gene deletion in mice revealed that EphrinB2/EphB4 signalling is dispensable for blood endothelial barrier function, but required for stabilization of lymphatic endothelial cell (LEC) junctions in different organs of juvenile and adult mice. Studies in primary human LECs further showed that basal EphrinB2/EphB4 signalling controls junctional localisation of the tight junction protein CLDN5 and junction stability via Rac1/Rho-mediated regulation of cytoskeletal contractility. EphrinB2/EphB4 signalling therefore provides a potential therapeutic target to selectively modulate lymphatic vessel permeability and function.

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Series: eLife
ISSN: 2050-084X
ISSN-E: 2050-084X
ISSN-L: 2050-084X
Volume: 9
Article number: e57732
DOI: 10.7554/eLife.57732
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: Taija Mäkinen: Cancerfonden (CAN 2013/387), Knut och Alice Wallenbergs Stiftelse (2015.0030), Knut och Alice Wallenbergs Stiftelse (2018.0218), Vetenskapsrådet (542-2014-3535), H2020 European Research Council (ERC-2014-CoG-646849). Maike Frye: Lymphatic Education & Research Network, Horizon 2020 Framework Programme (840189). Simon Stritt: Deutsche Forschungsgemeinschaft (STR 1538/1-1), European Molecular Biology Organization (ALTF 86-2017). Jorge L Martínez-Torrecuadrada: Regional Government of Madrid (BIPEDD2 S2011/BMD-2312), European Social Fund. Lauri Eklund: Suomen Akatemia (310986). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Academy of Finland Grant Number: 310986
Detailed Information: 310986 (Academy of Finland Funding decision)
Copyright information: © Frye et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.