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

Abstract

The pathogenesis of numerous diseases is characterised by disruption of the junctions that form the endothelial cell (EC) barrier, the composition of which may differ greatly between organs. However, the expression level variability and precise contribution of different junctional proteins 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 in EC barrier patterning. Across tissues Claudin5 exhibited diminishing expression along the arteriovenous axis, which correlates with EC barrier integrity. Functional analysis identified tissue-specific differences in leakage patterning and response to agonist-induced leakage. We uncover that Claudin5 loss enhances agonist-induced leakage in an organotypic, vessel type-specific and size-selective manner in an inducible, EC-specific, knock-out mouse. Mechanistically, Claudin5 loss induces no change in junction ultrastructure but alters composition, with concomitant loss of zonula occludens-1 (ZO-1) expression and upregulation of VE-Cadherin. These findings uncover the organ-specific organisation of the EC barrier and distinct importance of Claudin5 in different vascular beds and will aid our ability to modify EC barrier stability in a targeted, organ-specific manner.

The phosphodiesterase 2A regulates lymphatic endothelial development via cGMP-mediated control of Notch signaling

“…Selective barrier control can be achieved through exclusive expression of junction-controlling molecules in different EC types (Hilfenhaus et al, 2018, Richards et al, 2022). However, other molecules, such as VE-cadherin (Frye et al, 2015, Hägerling et al, 2018) and EphB4 (Frye et al, 2020, Luxán et al, 2019), have been shown to have multifaceted roles in junctional regulation, despite similar expression patterns.…”

Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis

“…5 Charité -Universitätsmedizin Berlin, Berlin, Germany. 6 Institute for Molecular Bioscience, Division of Cell and Developmental Biology, The University of Queensland, Brisbane, Queensland, Australia. 7 Instituto de Medicina Molecular -João lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.…”

“…The maintenance of junctions and barrier function relies on junctional complexes consisting of cell-adhesion molecules formed between adjacent ECs. Tight junctions limit vascular leakage preferentially in the central nervous system (CNS) and in arteries and post-arterial capillaries in peripheral tissues [4][5][6] . Adherens junctions, formed by VE-cadherin and associated catenins, are crucial for regulating venous and capillary vascular permeability, leukocyte extravasation and collective cell migration [7][8][9][10][11][12][13] .…”