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Nat Commun ; 11(1): 3595, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681081

RESUMO

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 ß-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.


Assuntos
Células Endoteliais/metabolismo , Microvasos/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Animais , Feminino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Masculino , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , beta Catenina/genética , beta Catenina/metabolismo
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