TY - JOUR
T1 - Preservation of microvascular barrier function requires CD31 receptor-induced metabolic reprogramming
AU - Cheung, Kenneth C.P.
AU - Fanti, Silvia
AU - Mauro, Claudio
AU - Wang, Guosu
AU - Nair, Anitha S.
AU - Fu, Hongmei
AU - Angeletti, Silvia
AU - Spoto, Silvia
AU - Fogolari, Marta
AU - Romano, Francesco
AU - Aksentijevic, Dunja
AU - Liu, Weiwei
AU - Li, Baiying
AU - Cheng, Lixin
AU - Jiang, Liwen
AU - Vuononvirta, Juho
AU - Poobalasingam, Thanushiyan R.
AU - Smith, David M.
AU - Ciccozzi, Massimo
AU - Solito, Egle
AU - Marelli-Berg, Federica M.
N1 - Funding Information:
This work was supported by funds from the British Heart Foundation (FS/11/64/2894). F.M.B. is the recipient of the British Heart Foundation Chair of Cardiovascular Immunology (CH/15/2/32064). E.S. is supported by Fondazione Italiana Sclerosi Multipla-FISM (2014/R/21). C.M. is supported by the BHF (FS/12/38/29640). We gratefully acknowledge the support offered by the CMR Advanced Bioimaging Facility, part of QMUL’s Advanced Molecular Imaging Service, for both their expertise and infrastructure and we would like to thank Julius Keswich for his excellent technical support and by Caterina Berg for her help with the figures.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/7/17
Y1 - 2020/7/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088030465&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-17329-8
DO - 10.1038/s41467-020-17329-8
M3 - Journal article
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3595
ER -
