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

Nature Communications
Kenneth C P CheungFederica M Marelli-Berg

Abstract

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.

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Citations

Oct 19, 2020·The American Journal of Pathology·Colin E EvansYou-Yang Zhao
Jun 24, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Reece P StevensJi Young Lee
Jun 8, 2021·Physiological Genomics·Uchenna EmechebeAnthony P Barnes
Sep 24, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Tsubasa OchiaiShuntaro Hara

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Datasets Mentioned

BETA
AB331646
AB2563179
AB10060377

Methods Mentioned

BETA
GTPase
fluorescence microscopy
glycosylation
flow cytometry
nuclear translocation
ubiquitination
ELISA
FCS
Assay
PCR

Software Mentioned

Primer 3Plus
Axiovision
ImageJ
GraphPad
Prism
FlowJo

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