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Nat Commun. 2017 Dec 15;8(1):2149. doi: 10.1038/s41467-017-01742-7.

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

Fang JS1,2,3,4, Coon BG1,2,3, Gillis N1,2,3,4, Chen Z5, Qiu J1,2,3,4,6, Chittenden TW5,7,8, Burt JM9, Schwartz MA1,2,3,10,11, Hirschi KK12,13,14,15,16,17.

Author information

1
Department of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
2
Yale Cardiovascular Research Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
3
Vascular Biology and Therapeutics Program, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
4
Yale Stem Cell Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
5
Computational Statistics and Bioinformatics Group, Advanced Artificial Intelligence Research Laboratory, WuXi NextCODE 55 Cambridge Parkway, 8th Floor, Cambridge, MA, 02142, USA.
6
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
7
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, A-111, 25 Shattuck Street, Boston, MA, 02115, USA.
8
Department of Biological Engineering, Massachusetts Institute of Technology, 21 Ames Street #56-651, Cambridge, MA, 02142, USA.
9
Department of Physiology, College of Medicine, The University of Arizona, 1501 N. Campbell Road, Tucson, AZ, 85724, USA.
10
Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
11
Department of Biomedical Engineering, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
12
Department of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA. karen.hirschi@yale.edu.
13
Yale Cardiovascular Research Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA. karen.hirschi@yale.edu.
14
Vascular Biology and Therapeutics Program, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA. karen.hirschi@yale.edu.
15
Yale Stem Cell Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA. karen.hirschi@yale.edu.
16
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA. karen.hirschi@yale.edu.
17
Department of Biomedical Engineering, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA. karen.hirschi@yale.edu.

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.

PMID:
29247167
PMCID:
PMC5732288
DOI:
10.1038/s41467-017-01742-7
[Indexed for MEDLINE]
Free PMC Article

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