Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification

Jennifer S. Fang, Brian G. Coon, Noelle Gillis, Zehua Chen, Jingyao Qiu, Thomas W. Chittenden, Janis M. Burt, Martin A. Schwartz and Karen K. Hirschi ()
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Jennifer S. Fang: Yale University School of Medicine
Brian G. Coon: Yale University School of Medicine
Noelle Gillis: Yale University School of Medicine
Zehua Chen: WuXi NextCODE 55 Cambridge Parkway
Jingyao Qiu: Yale University School of Medicine
Thomas W. Chittenden: WuXi NextCODE 55 Cambridge Parkway
Janis M. Burt: College of Medicine, The University of Arizona
Martin A. Schwartz: Yale University School of Medicine
Karen K. Hirschi: Yale University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Establishment 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.

Date: 2017
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DOI: 10.1038/s41467-017-01742-7

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