Claudin5 protects the peripheral endothelial barrier in an organ and vessel type-specific manner
- Uppsala University, Sweden
- University of Oulu, Finland
Abstract
Dysfunctional and leaky blood vessels resulting from disruption of the endothelial cell (EC) barrier accompanies numerous diseases. The EC barrier is established through endothelial cell tight and adherens junctions. However, the expression patterning and precise contribution of different junctional proteins to the EC barrier is poorly understood. Here, we focus on organs with continuous endothelium to identify structural and functional in vivo characteristics of the EC barrier. Assembly of multiple single-cell RNAseq datasets into a single integrated database revealed the variability and commonalities of EC barrier patterning. Across tissues, Claudin5 exhibited diminishing expression along the arteriovenous axis, correlating with EC barrier integrity. Functional analysis identified tissue-specific differences in leakage patterning and response to the leakage agonist histamine. Loss of Claudin5 enhanced histamine-induced leakage in an organotypic and vessel type-specific manner in an inducible, EC-specific, knock-out mouse. Mechanistically, Claudin5 loss left junction ultrastructure unaffected but altered its composition, with concomitant loss of zonula occludens-1 and upregulation of VE-Cadherin expression. These findings uncover the organ-specific organisation of the EC barrier and distinct importance of Claudin5 in different vascular beds, providing insights to modify EC barrier stability in a targeted, organ-specific manner.
Data availability
The murine ear skin data has been deposited in GEO under accession number GSE202290. Further details regarding specifics of the analysis will be available upon reasonable request.
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Claudin5 protects the peripheral endothelial barrier in an organ and vessel type-specific mannerNCBI Gene Expression Omnibus, GSE202290.
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A single-cell transcriptomic atlas characterizes ageing tissues in the mouseGene Expression Omnibus, GSE132042.
Article and author information
Author details
Katarzyna Koltowska
Lena Claesson-Welsh
Funding
Vetenskapsrådet (2020-01349)
- Lena Claesson-Welsh
Åke Wiberg Stiftelse (M21-0109)
- Sofia Nordling
Svenska Sällskapet för Medicinsk Forskning
- Elin Sjöberg
Svenska Sällskapet för Medicinsk Forskning (201912)
- Mark Richards
European Molecular Biology Organization (ALTF 923-2016)
- Mark Richards
Knut och Alice Wallenbergs Stiftelse (2020.0057)
- Lena Claesson-Welsh
Knut och Alice Wallenbergs Stiftelse (2019.0276)
- Lena Claesson-Welsh
Fondation Leducq (17 CVD 03)
- Lena Claesson-Welsh
Cancerfonden (19 0119 Pj)
- Lena Claesson-Welsh
Cancerfonden (19 0118 Us)
- Lena Claesson-Welsh
Cancerfonden (20 1086 Pj)
- Marleen Gloger
- Katarzyna Koltowska
Knut och Alice Wallenbergs Stiftelse (2017.0144)
- Katarzyna Koltowska
Ragnar Söderbergs stiftelse (M13/17)
- Katarzyna Koltowska
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: In vivo animal experiments were carried out in accordance with the ethical permit provided by the Committee on the Ethics of Animal Experiments of the University of Uppsala (permit 6789/18).
Reviewing Editor
- Gou Young Koh, Institute of Basic Science and Korea Advanced Institute of Science and Technology (KAIST), Korea (South), Republic of
Publication history
- Received: March 10, 2022
- Preprint posted: March 16, 2022 (view preprint)
- Accepted: July 20, 2022
- Accepted Manuscript published: July 21, 2022 (version 1)
- Version of Record published: August 3, 2022 (version 2)
Copyright
© 2022, Richards et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Claudin5 protects the peripheral endothelial barrier in an organ and vessel type-specific manner
eLife 11:e78517.
https://doi.org/10.7554/eLife.78517
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