Endothelial-Specific EphA4 Negatively Regulates Native Pial Collateral Formation and Re-Perfusion following Hindlimb Ischemia

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dc.contributor.authorOkyere, Benjaminen
dc.contributor.authorGiridhar, Kaavyaen
dc.contributor.authorHazy, Amandaen
dc.contributor.authorChen, Miaoen
dc.contributor.authorKeimig, Daviden
dc.contributor.authorBielitz, Robert C.en
dc.contributor.authorXie, Hehuangen
dc.contributor.authorHe, Jia-Qiangen
dc.contributor.authorHuckle, William R.en
dc.contributor.authorTheus, Michelle H.en
dc.date.accessioned2017-01-24T14:01:07Zen
dc.date.available2017-01-24T14:01:07Zen
dc.date.issued2016-07-28en
dc.description.abstractLeptomeningeal anastomoses play a critical role in regulating vascular re-perfusion following obstruction, however, the mechanisms regulating their development remains under investingation. Our current findings indicate that EphA4 receptor is a novel negative regulator of collaterogenesis. We demonstrate that EphA4 is highly expressed on pial arteriole collaterals at post-natal day (P) 1 and 7, then significantly reduced by P21. Endothelial cell (EC)-specific loss of EphA4, EphA4f/f/Tie2::Cre (KO), resulted in an increase in the density but not diameter of pial collaterals compared to WT mice. ECs isolated from KO mice displayed a 3-fold increase in proliferation, enhanced migration, tube formation and elevated levels of phospho(p)-Akt compared to WT ECs. Attenuating p-Akt, using LY294002, reduced the proliferative and migration effects in the KO ECs. RNAseq analysis also revealed altered expression patterns for genes that regulate cell proliferation, vascular development, extracellular matrix and immune-mediate responses, namely MCP-1, MMP2 and angiopoietin-1. Lastly, we show that induction of hindlimb ischemia resulted in accelerated re-perfusion, collateral remodeling and reduced tissue necrosis in the absence of ECspecific EphA4 compared to WT mice. These findings demonstrate a novel role for EphA4 in the early development of the pial collateral network and suggests a role in regulating vascular remodeling after obstruction.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0159930en
dc.identifier.issn1932-6203en
dc.identifier.issue7en
dc.identifier.urihttp://hdl.handle.net/10919/74413en
dc.identifier.volume11en
dc.language.isoenen
dc.publisherPLOSen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000381516100074&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectSMOOTH-MUSCLE-CELLen
dc.subjectRECEPTOR TYROSINE KINASESen
dc.subjectCENTRAL-NERVOUS-SYSTEMen
dc.subjectBLOOD-VESSEL FORMATIONen
dc.subjectGROWTH FACTOR-Aen
dc.subjectTUBE FORMATIONen
dc.subjectVASCULAR MORPHOGENESISen
dc.subjectINDUCED ANGIOGENESISen
dc.subjectSIGNALING PATHWAYSen
dc.subjectCOMMISSURAL AXONSen
dc.titleEndothelial-Specific EphA4 Negatively Regulates Native Pial Collateral Formation and Re-Perfusion following Hindlimb Ischemiaen
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeTexten
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Biocomplexity Instituteen
pubs.organisational-group/Virginia Tech/University Research Institutes/Biocomplexity Institute/Researchersen
pubs.organisational-group/Virginia Tech/University Research Institutes/Biocomplexity Institute/SelectedFaculty1en
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/CVM T&R Facultyen

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