These transmembrane proteins also associate with intracellular scaffolding and signaling proteins, as well as the cytoskeleton, which regulate their localisation and stability. EC barrier integrity is mediated primarily by adherens junctions (AJs) and tight junctions (TJs), composed of transmembrane proteins forming intercellular interactions that bridge adjacent EC membranes ( Corada et al., 1999 Claesson-Welsh et al., 2021). Loss of EC barrier integrity in-turn leads to enhanced molecular and cellular passage across the endothelium resulting in edema, tissue damage, atrophy, and disease progression ( Wu et al., 2014 Fleckenstein et al., 2018).
In such pathologies, local concentrations of inflammatory cytokines and growth factors are increased, leading to weakening of the endothelial cell (EC) barrier, a regulatable interface between circulating blood and the surrounding tissue environment ( Senger et al., 1983 Miles and Miles, 1952 Palade et al., 1979). Editor's evaluationīlood vessel dysfunction is a hallmark and contributing factor to the progression of numerous pathologies including solid tumours, ischemic diseases and inflammatory conditions ( Lee et al., 2007 Burke and Miles, 1958 Hashizume et al., 2000). 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. Mechanistically, Claudin5 loss left junction ultrastructure unaffected but altered its composition, with concomitant loss of zonula occludens-1 and upregulation of VE-Cadherin expression.
Loss of Claudin5 enhanced histamine-induced leakage in an organotypic and vessel type-specific manner in an inducible, EC-specific, knock-out mouse. Functional analysis identified tissue-specific differences in leakage properties and response to the leakage agonist histamine.
Across tissues, Claudin5 exhibited diminishing expression along the arteriovenous axis, correlating with EC barrier integrity. Assembly of multiple single-cell RNAseq datasets into a single integrated database revealed the variability and commonalities of EC barrier patterning. Here, we focus on organs with continuous endothelium to identify structural and functional in vivo characteristics of the EC barrier. However, the expression pattern and precise contribution of different junctional proteins to the EC barrier is poorly understood. The EC barrier is established through endothelial cell tight and adherens junctions. Dysfunctional and leaky blood vessels resulting from disruption of the endothelial cell (EC) barrier accompanies numerous diseases.
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