Preservation of microvascular barrier function requires CD31 receptor-induced metabolic reprogramming.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 07 2020
17 07 2020
Historique:
received:
01
05
2019
accepted:
09
06
2020
entrez:
19
7
2020
pubmed:
19
7
2020
medline:
20
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32681081
doi: 10.1038/s41467-020-17329-8
pii: 10.1038/s41467-020-17329-8
pmc: PMC7367815
doi:
Substances chimiques
Forkhead Box Protein O1
0
Platelet Endothelial Cell Adhesion Molecule-1
0
beta Catenin
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3595Subventions
Organisme : British Heart Foundation
ID : CH/15/2/32064
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/11/64/2894
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/14/2/30616
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P021220/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/12/38/29640
Pays : United Kingdom
Références
Trani, M. & Dejana, E. New insights in the control of vascular permeability: vascular endothelial-cadherin and other players. Curr. Opin. Hematol. 22, 267–272 (2015).
pubmed: 25767951
doi: 10.1097/MOH.0000000000000137
Vestweber, D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 15, 692–704 (2015).
pubmed: 26471775
doi: 10.1038/nri3908
Di Lorenzo, A., Fernandez-Hernando, C., Cirino, G. & Sessa, W. C. Akt1 is critical for acute inflammation and histamine-mediated vascular leakage. Proc. Natl Acad. Sci. USA 106, 14552–14557 (2009).
pubmed: 19622728
doi: 10.1073/pnas.0904073106
pmcid: 2732859
Yao, L. et al. Elevated CXCL1 expression in gp130-deficient endothelial cells impairs neutrophil migration in mice. Blood 122, 3832–3842 (2013).
pubmed: 24081661
pmcid: 3843240
doi: 10.1182/blood-2012-12-473835
Ma, L. et al. CD31 exhibits multiple roles in regulating T lymphocyte trafficking in-vivo. J. Immunol. 189, 4104–4111 (2012).
pubmed: 22966083
pmcid: 3496211
doi: 10.4049/jimmunol.1201739
Reed, E. F. Signal transduction via MHC-class-I molecules in endothelial and smooth muscle cells. Crit. Rev. Immunol. 23, 109–128 (2003).
pubmed: 12906262
doi: 10.1615/CritRevImmunol.v23.i12.60
Fishbein, G. A. & Fishbein, M. C. Morphologic and immunohistochemical findings in antibody-mediated rejection of the cardiac allograft. Hum. Immunol. 73, 1213–1217 (2012).
pubmed: 22813651
doi: 10.1016/j.humimm.2012.07.011
Mundinger, G. S. & Drachenberg, C. B. Chronic rejection in vascularized composite allografts. Curr. Opin. organ Transplant. 19, 309–314 (2014).
pubmed: 24811439
doi: 10.1097/MOT.0000000000000073
Ramirez-Sandoval, J. C., Varela-Jimenez, R. & Morales-Buenrostro, L. E. Capillary leak syndrome as a complication of antibody-mediated rejection treatment: a case report. CEN Case Rep. 7, 110–113 (2018).
pubmed: 29344912
pmcid: 5886937
doi: 10.1007/s13730-018-0306-5
Schnittler, H. Contraction of endothelial cells: 40 years of research, but the debate still lives. Histochemistry cell Biol. 146, 651–656 (2016).
doi: 10.1007/s00418-016-1501-0
Thurston, G. Complementary actions of VEGF and angiopoietin-1 on blood vessel growth and leakage. J. Anat. 200, 575–580 (2002).
pubmed: 12162725
pmcid: 1570748
doi: 10.1046/j.1469-7580.2002.00061.x
Liu, S. F. & Malik, A. B. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell Mol. Physiol. 290, L622–L645 (2006).
pubmed: 16531564
doi: 10.1152/ajplung.00477.2005
Muller, W. A. Leukocyte-endothelial cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 24, 326–333 (2003).
doi: 10.1016/S1471-4906(03)00117-0
Wong, M. X., Roberts, D., Bartley, P. A. & Jackson, D. E. Absence of platelet endothelial cell adhesion molecule-1 (CD31) leads to increased severity of local and systemic IgE-mediated anaphylaxis and modulation of masT-cell activation. J. Immunol. 168, 6455–6462 (2002).
pubmed: 12055265
doi: 10.4049/jimmunol.168.12.6455
Privratsky, J. R. et al. Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity. J. Cell Sci. 124, 1477–1485 (2011).
pubmed: 21486942
pmcid: 3078814
doi: 10.1242/jcs.082271
Maas, M. et al. Endothelial cell PECAM-1 confers protection against endotoxic shock. Am. J. Physiol. Heart Circ. Physiol. 288, H159–H164 (2005).
pubmed: 15319204
doi: 10.1152/ajpheart.00500.2004
Carrithers, M. et al. Enhanced susceptibility to endotoxic shock and impaired STAT3 signaling in CD31-deficient mice. Am. J. Pathol. 166, 185–196 (2005).
pubmed: 15632011
pmcid: 1602311
doi: 10.1016/S0002-9440(10)62243-2
Tada, Y. et al. Acceleration of the onset of collagen-induced arthritis by a deficiency of platelet endothelial cell adhesion molecule 1. Arthritis Rheum. 48, 3280–3290 (2003).
pubmed: 14613294
doi: 10.1002/art.11268
Graesser, D. et al. Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1-deficient mice. J. Clin. Invest 109, 383–392 (2002).
pubmed: 11827998
pmcid: 150854
doi: 10.1172/JCI0213595
Marelli-Berg, F. M., Peek, E., Lidington, E. A., Stauss, H. J. & Lechler, R. I. Isolation of endothelial cells from murine tissue. J. Immunol. Methods 244, 205–215 (2000).
pubmed: 11033033
doi: 10.1016/S0022-1759(00)00258-1
Mehta, D. & Malik, A. B. Signaling mechanisms regulating endothelial permeability. Physiol. Rev. 86, 279–367 (2006).
pubmed: 16371600
doi: 10.1152/physrev.00012.2005
Ziegler, M. E., Jin, Y. P., Young, S. H., Rozengurt, E. & Reed, E. F. HLA class I-mediated stress fiber formation requires ERK1/2 activation in the absence of an increase in intracellular Ca2+ in human aortic endothelial cells. Am. J. Physiol. Cell Physiol. 303, C872–C882 (2012).
pubmed: 22914643
pmcid: 3469712
doi: 10.1152/ajpcell.00199.2012
Hoftberger, R. et al. Expression of major histocompatibility complex class I molecules on the differenT-cell types in multiple sclerosis lesions. Brain Pathol. 14, 43–50 (2004).
pubmed: 14997936
doi: 10.1111/j.1750-3639.2004.tb00496.x
Male, D. K., Pryce, G. & Hughes, C. C. Antigen presentation in brain: MHC induction on brain endothelium and astrocytes compared. Immunology 60, 453–459 (1987).
pubmed: 3106198
pmcid: 1453249
Hordijk, P. L. et al. Vascular-endothelial-cadherin modulates endothelial monolayer permeability. J. Cell Sci. 112, 1915–1923 (1999).
pubmed: 10341210
doi: 10.1242/jcs.112.12.1915
Biswas, P. et al. PECAM-1 affects GSK-3beta-mediated beta-catenin phosphorylation and degradation. Am. J. Pathol. 169, 314–324 (2006).
pubmed: 16816383
pmcid: 1698776
doi: 10.2353/ajpath.2006.051112
Newman, D. K. et al. Nitration of PECAM-1 ITIM tyrosines abrogates phosphorylation and SHP-2 binding. Biochem Biophys. Res Commun. 296, 1171–1179 (2002).
pubmed: 12207897
doi: 10.1016/S0006-291X(02)02060-0
Dasgupta, B., Dufour, E., Mamdouh, Z. & Muller, W. A. A novel and critical role for tyrosine 663 in platelet endothelial cell adhesion molecule-1 trafficking and transendothelial migration. J. Immunol. 182, 5041–5051 (2009).
pubmed: 19342684
doi: 10.4049/jimmunol.0803192
Baumeister, U. et al. Association of Csk to VE-cadherin and inhibition of cell proliferation. EMBO J. 24, 1686–1695 (2005).
pubmed: 15861137
pmcid: 1142580
doi: 10.1038/sj.emboj.7600647
Potter, M. D., Barbero, S. & Cheresh, D. A. Tyrosine phosphorylation of VE-cadherin prevents binding of p120- and beta-catenin and maintains the cellular mesenchymal state. J. Biol. Chem. 280, 31906–31912 (2005).
pubmed: 16027153
doi: 10.1074/jbc.M505568200
De Bock, K. et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154, 651–663 (2013).
pubmed: 23911327
doi: 10.1016/j.cell.2013.06.037
Wilhelm, K. et al. FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature 529, 216–220 (2016).
pubmed: 26735015
pmcid: 5380221
doi: 10.1038/nature16498
Eelen, G., de Zeeuw, P., Simons, M. & Carmeliet, P. Endothelial cell metabolism in normal and diseased vasculature. Circ. Res 116, 1231–1244 (2015).
pubmed: 25814684
pmcid: 4380230
doi: 10.1161/CIRCRESAHA.116.302855
Ward, P. S. & Thompson, C. B. Signaling in control of cell growth and metabolism. Cold Spring Harb. Perspect. Biol. 4, a006783 (2012).
pubmed: 22687276
pmcid: 3385956
doi: 10.1101/cshperspect.a006783
den Hoed, M. et al. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nat. Genet. 45, 621–631 (2013).
doi: 10.1038/ng.2610
Devaux, Y. et al. Long noncoding RNAs in cardiac development and ageing. Nat. Rev. Cardiol. 12, 415–425 (2015).
pubmed: 25855606
doi: 10.1038/nrcardio.2015.55
Timmerman, I. et al. The tyrosine phosphatase SHP2 regulates recovery of endothelial adherens junctions through control of beta-catenin phosphorylation. Mol. Biol. Cell 23, 4212–4225 (2012).
pubmed: 22956765
pmcid: 3484100
doi: 10.1091/mbc.e12-01-0038
Wojtas, K., Slepecky, N., von Kalm, L. & Sullivan, D. Flight muscle function in Drosophila requires colocalization of glycolytic enzymes. Mol. Biol. Cell 8, 1665–1675 (1997).
pubmed: 9307964
pmcid: 305727
doi: 10.1091/mbc.8.9.1665
Cheung, K. et al. CD31 signals confer immune privilege to the vascular endothelium. Proc. Natl Acad. Sci. USA 112, E5815–E5824 (2015).
pubmed: 26392551
doi: 10.1073/pnas.1504777112
pmcid: 4629379
Osthus, R. C. et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J. Biol. Chem. 275, 21797–21800 (2000).
pubmed: 10823814
doi: 10.1074/jbc.C000023200
Ji, S. et al. ALDOA functions as an oncogene in the highly metastatic pancreatic cancer. Cancer Lett. 374, 127–135 (2016).
pubmed: 26854714
doi: 10.1016/j.canlet.2016.01.054
Clevers, H. Wnt/beta-catenin signaling in development and disease. Cell 127, 469–480 (2006).
pubmed: 17081971
doi: 10.1016/j.cell.2006.10.018
MacDonald, B. T., Tamai, K. & He, X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 (2009).
pubmed: 19619488
pmcid: 2861485
doi: 10.1016/j.devcel.2009.06.016
Dang, C. V., Le, A. & Gao, P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin. Cancer Res 15, 6479–6483 (2009).
pubmed: 19861459
pmcid: 2783410
doi: 10.1158/1078-0432.CCR-09-0889
Shirwany, N. A. & Zou, M. H. AMPK: a cellular metabolic and redox sensor. A minireview. Front Biosci. (Landmark Ed.) 19, 447–474 (2014).
doi: 10.2741/4218
Edmunds, L. R. et al. c-Myc programs fatty acid metabolism and dictates acetyl-CoA abundance and fate. J. Biol. Chem. 289, 25382–25392 (2014).
pubmed: 25053415
pmcid: 4155699
doi: 10.1074/jbc.M114.580662
Edmunds, L. R. et al. c-Myc and AMPK control cellular energy levels by cooperatively regulating mitochondrial structure and function. PLoS ONE 10, e0134049 (2015).
pubmed: 26230505
pmcid: 4521957
doi: 10.1371/journal.pone.0134049
Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262 (2012).
pubmed: 22436748
pmcid: 5726489
doi: 10.1038/nrm3311
Ouchi, N. et al. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J. Biol. Chem. 279, 1304–1309 (2004).
pubmed: 14557259
doi: 10.1074/jbc.M310389200
Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest 108, 1167–1174 (2001).
pubmed: 11602624
pmcid: 209533
doi: 10.1172/JCI13505
Johnson, D. B. et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N. Engl. J. Med 375, 1749–1755 (2016).
pubmed: 27806233
pmcid: 5247797
doi: 10.1056/NEJMoa1609214
Valujskikh, A., Lantz, O., Celli, S., Matzinger, P. & Heeger, P. S. Cross-primed CD8(+) T-cells mediate graft rejection via a distinct effector pathway. Nat. Immunol. 3, 844–851 (2002).
pubmed: 12172545
doi: 10.1038/ni831
Opal, S. M. & van der Poll, T. Endothelial barrier dysfunction in septic shock. J. Intern Med 277, 277–293 (2015).
pubmed: 25418337
doi: 10.1111/joim.12331
Collins, C. et al. Localized tensional forces on PECAM-1 elicit a global mechanotransduction response via the integrin-RhoA pathway. Curr. Biol. 22, 2087–2094 (2012).
pubmed: 23084990
pmcid: 3681294
doi: 10.1016/j.cub.2012.08.051
Lacolley, P. Mechanical influence of cyclic stretch on vascular endothelial cells. Cardiovasc. Res. 63, 577–579 (2004).
pubmed: 15306211
doi: 10.1016/j.cardiores.2004.06.017
Sun, W., Li, F. S., Zhang, Y. H., Wang, X. P. & Wang, C. R. Association of susceptibility to septic shock with platelet endothelial cell adhesion molecule-1 gene Leu125Val polymorphism and serum sPECAM-1 levels in sepsis patients. Int J. Clin. Exp. Med. 8, 20490–20498 (2015).
pubmed: 26884965
pmcid: 4723810
Privratsky, J. R., Newman, D. K. & Newman, P. J. PECAM-1: conflicts of interest in inflammation. Life Sci. 87, 69–82 (2010).
pubmed: 20541560
pmcid: 2917326
doi: 10.1016/j.lfs.2010.06.001
Tzivion, G., Dobson, M. & Ramakrishnan, G. FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. Biochim Biophys. Acta 1813, 1938–1945 (2011).
pubmed: 21708191
doi: 10.1016/j.bbamcr.2011.06.002
Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. & Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785–789 (1995).
pubmed: 8524413
doi: 10.1038/378785a0
Monick, M. M. et al. Lipopolysaccharide activates Akt in human alveolar macrophages resulting in nuclear accumulation and transcriptional activity of beta-catenin. J. Immunol. 166, 4713–4720 (2001).
pubmed: 11254732
doi: 10.4049/jimmunol.166.7.4713
Novellasdemunt, L. et al. PFKFB3 activation in cancer cells by the p38/MK2 pathway in response to stress stimuli. Biochem J. 452, 531–543 (2013).
pubmed: 23548149
doi: 10.1042/BJ20121886
Greer, E. L. & Brunet, A. FOXO transcription factors in ageing and cancer. Acta Physiol. (Oxf.) 192, 19–28 (2008).
doi: 10.1111/j.1748-1716.2007.01780.x
Caja, S. & Enriquez, J. A. Mitochondria in endothelial cells: Sensors and integrators of environmental cues. Redox Biol. 12, 821–827 (2017).
pubmed: 28448943
pmcid: 5406579
doi: 10.1016/j.redox.2017.04.021
Diebold, L. P. et al. Mitochondrial complex III is necessary for endothelial cell proliferation during angiogenesis. Nat. Metabolism 1, 158–171 (2019).
Dimaio, T. A. et al. Attenuation of retinal vascular development and neovascularization in PECAM-1-deficient mice. Dev. Biol. 315, 72–88 (2008).
pubmed: 18206868
pmcid: 2275901
doi: 10.1016/j.ydbio.2007.12.008
Woodfin, A. et al. Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1. Blood 113, 6246–6257 (2009).
pubmed: 19211506
pmcid: 2699241
doi: 10.1182/blood-2008-11-188375
Barzilai, S. et al. Leukocytes breach endothelial barriers by insertion of nuclear lobes and disassembly of endothelial actin filaments. Cell Rep. 18, 685–699 (2017).
pubmed: 28099847
doi: 10.1016/j.celrep.2016.12.076
Schnoor, M. et al. Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in-vivo. J. Exp. Med 208, 1721–1735 (2011).
pubmed: 21788407
pmcid: 3149227
doi: 10.1084/jem.20101920
Seidowsky, A., Nseir, S., Houdret, N. & Fourrier, F. Metformin-associated lactic acidosis: a prognostic and therapeutic study. Crit. Care Med. 37, 2191–2196 (2009).
pubmed: 19487945
doi: 10.1097/CCM.0b013e3181a02490
Park, J. et al. Impact of Metformin Use on Lactate Kinetics in Patients with Severe Sepsis and Septic. Shock. Shock. 47, 582–587 (2017).
pubmed: 27792125
doi: 10.1097/SHK.0000000000000782
Tang, G. et al. Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway. Oncotarget 8, 97977–97989 (2017).
pubmed: 29228667
pmcid: 5716707
doi: 10.18632/oncotarget.20105
Rizzo, A. N., Aman, J., van Nieuw Amerongen, G. P. & Dudek, S. M. Targeting Abl kinases to regulate vascular leak during sepsis and acute respiratory distress syndrome. Arterioscler Thromb. Vasc. Biol. 35, 1071–1079 (2015).
pubmed: 25814671
pmcid: 4655821
doi: 10.1161/ATVBAHA.115.305085
Kim, I. K. et al. Effect of tyrosine kinase inhibitors, imatinib and nilotinib, in murine lipopolysaccharide-induced acute lung injury during neutropenia recovery. Crit. Care 17, R114 (2013).
pubmed: 23787115
pmcid: 4056323
doi: 10.1186/cc12786
Aman, J. et al. Effective treatment of edema and endothelial barrier dysfunction with imatinib. Circulation 126, 2728–2738 (2012).
pubmed: 23099479
doi: 10.1161/CIRCULATIONAHA.112.134304
Letsiou, E. et al. Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 308, L259–L269 (2015).
pubmed: 25480336
doi: 10.1152/ajplung.00323.2014
Stephens, R. S. et al. Protein kinase G increases antioxidant function in lung microvascular endothelial cells by inhibiting the c-Abl tyrosine kinase. Am. J. Physiol. Cell Physiol. 306, C559–C569 (2014).
pubmed: 24401847
pmcid: 3948974
doi: 10.1152/ajpcell.00375.2012
Duncan, G. S. et al. Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions. J. Immunol. 162, 3022–3030 (1999).
pubmed: 10072554
Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402–408 (2001).
pubmed: 11846609
doi: 10.1006/meth.2001.1262
Billingham, R. & Medawar, P. B. The technique of free skin grafting in mammals. J. Exp. Biol. 28, 385–402 (1951).
doi: 10.1242/jeb.28.3.385