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dc.contributor.authorFang, Jennifer S.
dc.contributor.authorCoon, Brian G.
dc.contributor.authorGillis, Noelle
dc.contributor.authorChen, Zehua
dc.contributor.authorQiu, Jingyao
dc.contributor.authorChittenden, Thomas W.
dc.contributor.authorBurt, Janis M.
dc.contributor.authorSchwartz, Martin A.
dc.contributor.authorHirschi, Karen K.
dc.date.accessioned2018-01-31T17:24:19Z
dc.date.available2018-01-31T17:24:19Z
dc.date.issued2017-12-15
dc.identifier.citationShear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification 2017, 8 (1) Nature Communicationsen
dc.identifier.issn2041-1723
dc.identifier.pmid29247167
dc.identifier.doi10.1038/s41467-017-01742-7
dc.identifier.urihttp://hdl.handle.net/10150/626459
dc.description.abstractEstablishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.
dc.description.sponsorshipNIH [HL128064, HL096360, EB017103, U2EB017103, HL107205]; CT Innovations [15-RMB-YALE-04, 15-RMB-YALE-07]en
dc.language.isoenen
dc.publisherNATURE PUBLISHING GROUPen
dc.relation.urlhttp://www.nature.com/articles/s41467-017-01742-7en
dc.rights© The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License.en
dc.titleShear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specificationen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Dept Physiol, Coll Meden
dc.identifier.journalNature Communicationsen
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-04-12T10:33:49Z
html.description.abstractEstablishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.


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