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

Research output: Contribution to journalArticlepeer-review

Authors

  • Kenneth C P Cheung
  • Silvia Fanti
  • Guosu Wang
  • Anitha S Nair
  • Hongmei Fu
  • Silvia Angeletti
  • Silvia Spoto
  • Marta Fogolari
  • Francesco Romano
  • Dunja Aksentijevic
  • Weiwei Liu
  • Baiying Li
  • Lixin Cheng
  • Liwen Jiang
  • Juho Vuononvirta
  • Thanushiyan R Poobalasingam
  • David M Smith
  • Massimo Ciccozzi
  • Egle Solito
  • Federica M Marelli-Berg

Colleges, School and Institutes

External organisations

  • Queen Mary University
  • Institute for Inflammation and Ageing
  • Campus Bio-Medico University of Rome
  • Sun Yat-sen University Cancer Center
  • AstraZeneca
  • The Chinese University of Hong Kong

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.

Details

Original languageEnglish
Pages (from-to)3595
JournalNature Communications
Volume11
Issue number1
Publication statusPublished - 17 Jul 2020