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dc.rights.licenseopenen_US
hal.structure.identifierBiologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases
dc.contributor.authorCHAPOULY, Candice
dc.contributor.authorTADESSE ARGAW, Azeb
dc.contributor.authorHORNG, Sam
dc.contributor.authorCASTRO, Kamilah
dc.contributor.authorZHANG, Jingya
dc.contributor.authorASP, Linnea
dc.contributor.authorLOO, Hannah
dc.contributor.authorLAITMAN, Benjamin M.
dc.contributor.authorMARIANI, John N.
dc.contributor.authorSTRAUS FARBER, Rebecca
dc.contributor.authorZASLAVSKY, Elena
dc.contributor.authorNUDELMAN, German
dc.contributor.authorRAINE, Cedric S.
dc.contributor.authorJOHN, Gareth R.
dc.date.accessioned2020-10-27T10:49:52Z
dc.date.available2020-10-27T10:49:52Z
dc.date.issued2015-06
dc.identifier.issn1460-2156en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/11491
dc.description.abstractEnIn inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown.
dc.language.isoENen_US
dc.subjectArticle RECHERCHE
dc.subject.enAnimals
dc.subject.enAstrocyte
dc.subject.enAutoimmune
dc.subject.enBlood-Brain Barrier
dc.subject.enCells
dc.subject.enCerebral Cortex
dc.subject.enCultured
dc.subject.enDeoxyribose
dc.subject.enEncephalomyelitis
dc.subject.enEndothelial Cell Growth Factor
dc.subject.enEndothelium
dc.subject.enExperimental
dc.subject.enHumans
dc.subject.enInterleukin-1beta
dc.subject.enMice
dc.subject.enMultiple Sclerosis
dc.subject.enThymidine Phosphorylase
dc.subject.enTight Junction
dc.subject.enTranscriptional Activation
dc.subject.enTransgenic
dc.subject.enVascular
dc.subject.enVascular Endothelial Growth Factor A
dc.title.enAstrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions
dc.typeArticle de revueen_US
dc.identifier.doi10.1093/brain/awv077en_US
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologieen_US
dc.identifier.pubmed25805644en_US
bordeaux.journalBrainen_US
bordeaux.page1548–1567en_US
bordeaux.volume138en_US
bordeaux.hal.laboratoriesBiologie des maladies cardiovasculaires - U1034en_US
bordeaux.issuePt 6en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-02979785
hal.version1
hal.date.transferred2020-10-27T10:49:58Z
hal.exporttrue
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