Endothelial deletion of EPH receptor A4 alters single-cell profile and Tie2/Akap12 signaling to preserve blood-brain barrier integrity
dc.contributor.author | Cash, Alison | en |
dc.contributor.author | de Jager, Caroline | en |
dc.contributor.author | Brickler, Thomas | en |
dc.contributor.author | Soliman, Eman | en |
dc.contributor.author | Ladner, Liliana | en |
dc.contributor.author | Kaloss, Alexandra M. | en |
dc.contributor.author | Zhu, Yumeng | en |
dc.contributor.author | Pridham, Kevin J. | en |
dc.contributor.author | Mills, Jatia | en |
dc.contributor.author | Ju, Jing | en |
dc.contributor.author | Basso, Erwin Kristobal Gudenschwager | en |
dc.contributor.author | Chen, Michael | en |
dc.contributor.author | Johnson, Zachary | en |
dc.contributor.author | Sotiropoulos, Yianni | en |
dc.contributor.author | Wang, Xia | en |
dc.contributor.author | Xie, Hehuang | en |
dc.contributor.author | Matson, John B. | en |
dc.contributor.author | Marvin, Eric A. | en |
dc.contributor.author | Theus, Michelle H. | en |
dc.date.accessioned | 2025-05-09T19:38:44Z | en |
dc.date.available | 2025-05-09T19:38:44Z | en |
dc.date.issued | 2023-10-10 | en |
dc.description.abstract | Neurobiological 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.version | Published version | en |
dc.format.extent | 12 page(s) | en |
dc.format.mimetype | application/pdf | en |
dc.identifier | ARTN e2204700120 (Article number) | en |
dc.identifier.doi | https://doi.org/10.1073/pnas.2204700120 | en |
dc.identifier.eissn | 1091-6490 | en |
dc.identifier.issn | 0027-8424 | en |
dc.identifier.issue | 41 | en |
dc.identifier.orcid | Matson, John [0000-0001-7984-5396] | en |
dc.identifier.orcid | Theus, Michelle [0000-0001-6485-2104] | en |
dc.identifier.orcid | Marvin, Eric [0000-0002-6612-1337] | en |
dc.identifier.orcid | Xie, Hehuang [0000-0001-5739-1653] | en |
dc.identifier.pmid | 37796990 | en |
dc.identifier.uri | https://hdl.handle.net/10919/131413 | en |
dc.identifier.volume | 120 | en |
dc.language.iso | en | en |
dc.publisher | National Academy of Sciences | en |
dc.relation.uri | https://www.ncbi.nlm.nih.gov/pubmed/37796990 | en |
dc.rights | Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | en |
dc.subject | brain injury | en |
dc.subject | junction protein | en |
dc.subject | neuroprotection | en |
dc.subject.mesh | Blood-Brain Barrier | en |
dc.subject.mesh | Endothelial Cells | en |
dc.subject.mesh | Animals | en |
dc.subject.mesh | Mice, Knockout | en |
dc.subject.mesh | Mice | en |
dc.subject.mesh | Receptor, EphA4 | en |
dc.subject.mesh | Receptor, TIE-2 | en |
dc.subject.mesh | Cell Cycle Proteins | en |
dc.subject.mesh | A Kinase Anchor Proteins | en |
dc.subject.mesh | Brain Injuries, Traumatic | en |
dc.title | Endothelial deletion of EPH receptor A4 alters single-cell profile and Tie2/Akap12 signaling to preserve blood-brain barrier integrity | en |
dc.title.serial | PNAS | en |
dc.type | Article - Refereed | en |
dc.type.dcmitype | Text | en |
dc.type.other | Article | en |
dc.type.other | Journal | en |
pubs.organisational-group | Virginia Tech | en |
pubs.organisational-group | Virginia Tech/Science | en |
pubs.organisational-group | Virginia Tech/Science/Chemistry | en |
pubs.organisational-group | Virginia Tech/Veterinary Medicine | en |
pubs.organisational-group | Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiology | en |
pubs.organisational-group | Virginia Tech/Faculty of Health Sciences | en |
pubs.organisational-group | Virginia Tech/All T&R Faculty | en |
pubs.organisational-group | Virginia Tech/Science/COS T&R Faculty | en |
pubs.organisational-group | Virginia Tech/Veterinary Medicine/CVM T&R Faculty | en |
pubs.organisational-group | Virginia Tech/VT Carilion School of Medicine | en |
pubs.organisational-group | Virginia Tech/Report test | en |
pubs.organisational-group | Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiology/Other | en |
pubs.organisational-group | Virginia Tech/VT Carilion School of Medicine/Surgery | en |
pubs.organisational-group | Virginia Tech/VT Carilion School of Medicine/Surgery/Neurosurgery | en |