Endothelial deletion of EPH receptor A4 alters single-cell profile and Tie2/Akap12 signaling to preserve blood-brain barrier integrity

dc.contributor.authorCash, Alisonen
dc.contributor.authorde Jager, Carolineen
dc.contributor.authorBrickler, Thomasen
dc.contributor.authorSoliman, Emanen
dc.contributor.authorLadner, Lilianaen
dc.contributor.authorKaloss, Alexandra M.en
dc.contributor.authorZhu, Yumengen
dc.contributor.authorPridham, Kevin J.en
dc.contributor.authorMills, Jatiaen
dc.contributor.authorJu, Jingen
dc.contributor.authorBasso, Erwin Kristobal Gudenschwageren
dc.contributor.authorChen, Michaelen
dc.contributor.authorJohnson, Zacharyen
dc.contributor.authorSotiropoulos, Yiannien
dc.contributor.authorWang, Xiaen
dc.contributor.authorXie, Hehuangen
dc.contributor.authorMatson, John B.en
dc.contributor.authorMarvin, Eric A.en
dc.contributor.authorTheus, Michelle H.en
dc.date.accessioned2025-05-09T19:38:44Zen
dc.date.available2025-05-09T19:38:44Zen
dc.date.issued2023-10-10en
dc.description.abstractNeurobiological consequences of traumatic brain injury (TBI) result from a complex interplay of secondary injury responses and sequela that mediates chronic disability. Endothelial cells are important regulators of the cerebrovascular response to TBI. Our work demonstrates that genetic deletion of endothelial cell (EC)-specific EPH receptor A4 (EphA4) using conditional EphA4f/f/Tie2-Cre and EphA4f/f/VE-Cadherin-CreERT2 knockout (KO) mice promotes blood–brain barrier (BBB) integrity and tissue protection, which correlates with improved motor function and cerebral blood flow recovery following controlled cortical impact (CCI) injury. scRNAseq of capillary-derived KO ECs showed increased differential gene expression of BBB-related junctional and actin cytoskeletal regulators, namely, A-kinase anchor protein 12, Akap12, whose presence at Tie2 clustering domains is enhanced in KO microvessels. Transcript and protein analysis of CCI-injured whole cortical tissue or cortical-derived ECs suggests that EphA4 limits the expression of Cldn5, Akt, and Akap12 and promotes Ang2. Blocking Tie2 using sTie2-Fc attenuated protection and reversed Akap12 mRNA and protein levels cortical-derived ECs. Direct stimulation of Tie2 using Vasculotide, angiopoietin-1 memetic peptide, phenocopied the neuroprotection. Finally, we report a noteworthy rise in soluble Ang2 in the sera of individuals with acute TBI, highlighting its promising role as a vascular biomarker for early detection of BBB disruption. These findings describe a contribution of the axon guidance molecule, EphA4, in mediating TBI microvascular dysfunction through negative regulation of Tie2/Akap12 signaling.en
dc.description.versionPublished versionen
dc.format.extent12 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN e2204700120 (Article number)en
dc.identifier.doihttps://doi.org/10.1073/pnas.2204700120en
dc.identifier.eissn1091-6490en
dc.identifier.issn0027-8424en
dc.identifier.issue41en
dc.identifier.orcidMatson, John [0000-0001-7984-5396]en
dc.identifier.orcidTheus, Michelle [0000-0001-6485-2104]en
dc.identifier.orcidMarvin, Eric [0000-0002-6612-1337]en
dc.identifier.orcidXie, Hehuang [0000-0001-5739-1653]en
dc.identifier.pmid37796990en
dc.identifier.urihttps://hdl.handle.net/10919/131413en
dc.identifier.volume120en
dc.language.isoenen
dc.publisherNational Academy of Sciencesen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/37796990en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectbrain injuryen
dc.subjectjunction proteinen
dc.subjectneuroprotectionen
dc.subject.meshBlood-Brain Barrieren
dc.subject.meshEndothelial Cellsen
dc.subject.meshAnimalsen
dc.subject.meshMice, Knockouten
dc.subject.meshMiceen
dc.subject.meshReceptor, EphA4en
dc.subject.meshReceptor, TIE-2en
dc.subject.meshCell Cycle Proteinsen
dc.subject.meshA Kinase Anchor Proteinsen
dc.subject.meshBrain Injuries, Traumaticen
dc.titleEndothelial deletion of EPH receptor A4 alters single-cell profile and Tie2/Akap12 signaling to preserve blood-brain barrier integrityen
dc.title.serialPNASen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/Scienceen
pubs.organisational-groupVirginia Tech/Science/Chemistryen
pubs.organisational-groupVirginia Tech/Veterinary Medicineen
pubs.organisational-groupVirginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-groupVirginia Tech/Faculty of Health Sciencesen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/Science/COS T&R Facultyen
pubs.organisational-groupVirginia Tech/Veterinary Medicine/CVM T&R Facultyen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicineen
pubs.organisational-groupVirginia Tech/Report testen
pubs.organisational-groupVirginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiology/Otheren
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Surgeryen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Surgery/Neurosurgeryen

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