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

• DOI: 10.7554/elife.78517
• Publication Date: 2022-07-21T10:15:11Z
• Authors: Mark Richards; Emmanuel Nwadozi; Sagnik Pal; Pernilla Martinsson; Mika Kaakinen; Marleen Gloger; Elin Sjöberg; Katarzyna Koltowska; Christer Betsholtz; Lauri Eklund; Sofia Nordling; Lena Claesson-Welsh
• Keywords: 0301 basic medicine; QH301-705.5; Cell- och molekylärbiologi; Science; Biochemistry; Tight Junctions; organotypicity; Mice; 03 medical and health sciences; Animals; Claudin-5; Endothelium; Biology (General); Biokemi; Molecular Biology; vascular permeability; 0303 health sciences; Molekylärbiologi; Q; Biochemistry and Molecular Biology; R; Endothelial Cells; Claudin 5; Cell Biology; Adherens Junctions; Cadherins; endothelial cell; Medicine; Cell and Molecular Biology; Biokemi och molekylärbiologi; Histamine

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.