University of Oulu

Richards, M., Nwadozi, E., Pal, S., Martinsson, P., Kaakinen, M., Gloger, M., Sjöberg, E., Koltowska, K., Betsholtz, C., Eklund, L., Nordling, S., & Claesson-Welsh, L. (2022). Claudin5 protects the peripheral endothelial barrier in an organ and vessel-type-specific manner. ELife, 11, e78517.

Claudin5 protects the peripheral endothelial barrier in an organ and vessel-type-specific manner

Saved in:
Author: Richards, Mark1,2; Nwadozi, Emmanuel1,2; Pal, Sagnik1,2;
Organizations: 1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2Beijer Gene- and Neuro Laboratory and Science for Life Laboratories, Uppsala University, Uppsala, Sweden
3Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
4Department of Medicine Huddinge, Karolinska Institutet, Campus Flemingsberg, Neo, Huddinge, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 14.2 MB)
Persistent link:
Language: English
Published: eLife Sciences Publications, 2022
Publish Date: 2023-02-03


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 pattern 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 properties 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.

see all

Series: eLife
ISSN: 2050-084X
ISSN-E: 2050-084X
ISSN-L: 2050-084X
Volume: 11
Article number: 78517
DOI: 10.7554/elife.78517
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: The authors acknowledge the Biocenter Oulu Electron Microscopy Core Facility supported by Biocenter Finland and the University of Oulu for their specific scientific expertise and research infrastructure services and the equipment and expert advice supplied by the BioVis imaging and flow cytometry core facility (Uppsala University). This study was supported by the Swedish Research Council (2020–01349), the Knut and Alice Wallenberg foundation (KAW 2020.0057 and KAW 2019.0276), Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease (17 CVD 03) and the Swedish Cancer Society (Cancerfonden) 19 0119 Pj and 19 0118 Us to LC-W. KK and MG were supported by Cancerfonden (20 1,086 Pj), KK was supported by Wallenberg Academy Fellowship (2017.0144), Ragnar Söderbergs Fellowship (M13/17). ES was supported by Svenska Sällskapet för Medicinsk Forskning (SSMF). EN was supported by the Gustaf Adolf Johansson’s foundation. SN was supported by Åke Wibergs foundation (M21-0109). MR was supported by SSMF (201912) and an EMBO long-term fellowship (ALTF 923–2016).
Dataset Reference: 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.
Copyright information: © 2022, Richards 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.