TY - JOUR TI - Claudin5 protects the peripheral endothelial barrier in an organ and vessel-type-specific manner AU - Richards, Mark AU - Nwadozi, Emmanuel AU - Pal, Sagnik AU - Martinsson, Pernilla AU - Kaakinen, Mika AU - Gloger, Marleen AU - Sjöberg, Elin AU - Koltowska, Katarzyna AU - Betsholtz, Christer AU - Eklund, Lauri AU - Nordling, Sofia AU - Claesson-Welsh, Lena A2 - Koh, Gou Young A2 - Akhmanova, Anna A2 - Koh, Gou Young A2 - Saharinen, Pipsa VL - 11 PY - 2022 DA - 2022/07/21 SP - e78517 C1 - eLife 2022;11:e78517 DO - 10.7554/eLife.78517 UR - https://doi.org/10.7554/eLife.78517 AB - 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. KW - endothelial cell KW - vascular permeability KW - organotypicity KW - Claudin 5 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -