Preservation of microvascular barrier function requires CD31 receptor-induced metabolic reprogramming

Endothelial barrier (EB) breaching is a frequent event during inflammation, and it is followed by the rapid recovery of microvascular integrity. The molecular mechanisms of EB recovery are poorly understood. Triggering of MHC molecules by migrating T-cells is a minimal signal capable of inducing end...

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Published in:	Nature communications Vol. 11; no. 1; p. 3595
Main Authors:	Cheung, Kenneth C. P., Fanti, Silvia, Mauro, Claudio, Wang, Guosu, Nair, Anitha S., Fu, Hongmei, Angeletti, Silvia, Spoto, Silvia, Fogolari, Marta, Romano, Francesco, Aksentijevic, Dunja, Liu, Weiwei, Li, Baiying, Cheng, Lixin, Jiang, Liwen, Vuononvirta, Juho, Poobalasingam, Thanushiyan R., Smith, David M., Ciccozzi, Massimo, Solito, Egle, Marelli-Berg, Federica M.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 17-07-2020 Nature Publishing Group Nature Portfolio
Subjects:	101/28 13/1 13/31 13/51 13/95 14/19 14/28 14/63 631/80 631/80/84 64/60 692/420/256 96/106 Activation AKT protein Animals Antibodies beta Catenin - genetics beta Catenin - metabolism College campuses Contraction Endothelial cells Endothelial Cells - metabolism Endothelium Experiments Female Forkhead Box Protein O1 - genetics Forkhead Box Protein O1 - metabolism FOXO1 protein Glycolysis Homology Humanities and Social Sciences Inflammation Integrity Laboratories Leakage Lymphocytes T Major histocompatibility complex Male Metabolism Mice Microvasculature Microvessels - metabolism Mitochondria Molecular modelling multidisciplinary Permeability Phosphatase Phosphorylation Platelet Endothelial Cell Adhesion Molecule-1 - genetics Platelet Endothelial Cell Adhesion Molecule-1 - metabolism Polymerization Preservation Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Receptors Recovery Science Science (multidisciplinary) Signal Transduction Transcription Translocation β-Catenin
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Summary:	Endothelial barrier (EB) breaching is a frequent event during inflammation, and it is followed by the rapid recovery of microvascular integrity. The molecular mechanisms of EB recovery are poorly understood. Triggering of MHC molecules by migrating T-cells is a minimal signal capable of inducing endothelial contraction and transient microvascular leakage. Using this model, we show that EB recovery requires a CD31 receptor-induced, robust glycolytic response sustaining junction re-annealing. Mechanistically, this response involves src-homology phosphatase activation leading to Akt-mediated nuclear exclusion of FoxO1 and concomitant β-catenin translocation to the nucleus, collectively leading to cMyc transcription. CD31 signals also sustain mitochondrial respiration, however this pathway does not contribute to junction remodeling. We further show that pathologic microvascular leakage in CD31-deficient mice can be corrected by enhancing the glycolytic flux via pharmacological Akt or AMPK activation, thus providing a molecular platform for the therapeutic control of EB response. The mechanisms that restore endothelial barrier integrity following inflammation-induced breaching are incompletely understood. Here the authors show that the CD31 immune receptor contributes to reestablishing vascular integrity via its effects on endothelial cell metabolism.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-020-17329-8