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

Kenneth C. P. Cheung, Silvia Fanti, Claudio Mauro, 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 and Federica M. Marelli-Berg ()
Additional contact information
Kenneth C. P. Cheung: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Silvia Fanti: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Claudio Mauro: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Guosu Wang: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Anitha S. Nair: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Hongmei Fu: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Silvia Angeletti: University Campus Bio-Medico of Rome
Silvia Spoto: University campus Bio-Medico of Rome
Marta Fogolari: University Campus Bio-Medico of Rome
Francesco Romano: University Campus Bio-Medico of Rome
Dunja Aksentijevic: Queen Mary University of London
Weiwei Liu: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
Baiying Li: The Chinese University of Hong Kong
Lixin Cheng: The Chinese University of Hong Kong
Liwen Jiang: The Chinese University of Hong Kong
Juho Vuononvirta: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Thanushiyan R. Poobalasingam: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
David M. Smith: AstraZeneca R&D, Cambridge Science Park
Massimo Ciccozzi: University Campus Bio-Medico of Rome
Egle Solito: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Federica M. Marelli-Berg: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17329-8

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