Preservation of microvascular barrier function requires CD31 receptor-induced metabolic reprogramming
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- Queen Mary, University of London
- Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK.
- Centre for Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK.
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Centre, Charterhouse Square, London, UK.
- Institute for Inflammation and Ageing
- Institute of Translational Medicine and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Office 04, Ground Floor, ITM, North Block, Heritage Building, Mindelson Way, Edgbaston, Birmingham, B15 2TH, UK. firstname.lastname@example.org.
- Campus Bio-Medico University of Rome
- Sun Yat-sen University Cancer Center
- 1] Hong Kong Bioinformatics Centre, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong  5 CUHK-BGI Innovation Institute of Trans-omics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
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.
|Publication status||Published - 17 Jul 2020|