Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification
AuthorFang, Jennifer S.
Coon, Brian G.
Chittenden, Thomas W.
Burt, Janis M.
Schwartz, Martin A.
Hirschi, Karen K.
AffiliationUniv Arizona, Dept Physiol, Coll Med
MetadataShow full item record
PublisherNATURE PUBLISHING GROUP
CitationShear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification 2017, 8 (1) Nature Communications
Rights© The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License.
Collection InformationThis 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 email@example.com.
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.
VersionFinal published version
SponsorsNIH [HL128064, HL096360, EB017103, U2EB017103, HL107205]; CT Innovations [15-RMB-YALE-04, 15-RMB-YALE-07]