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, Karen K. Hirschi

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Article number2149
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Endothelial cells
notches
Cell Cycle Checkpoints
Blood Vessels
specifications
Endothelial Cells
shear
Specifications
Gene expression
cycles
Cell Cycle
Cells
gene expression
Gene Expression
Blood vessels
Tissue Engineering
Growth
Embryonic Development
Shear stress
engineering

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Fang, J. S., Coon, B. G., Gillis, N., Chen, Z., Qiu, J., Chittenden, T. W., ... Hirschi, K. K. (2017). Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification. Nature Communications, 8(1), [2149]. https://doi.org/10.1038/s41467-017-01742-7

Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification. / Fang, Jennifer S.; Coon, Brian G.; Gillis, Noelle; Chen, Zehua; Qiu, Jingyao; Chittenden, Thomas W.; Burt, Janis M; Schwartz, Martin A.; Hirschi, Karen K.

In: Nature Communications, Vol. 8, No. 1, 2149, 01.12.2017.

Research output: Contribution to journalArticle

Fang, JS, Coon, BG, Gillis, N, Chen, Z, Qiu, J, Chittenden, TW, Burt, JM, Schwartz, MA & Hirschi, KK 2017, 'Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification', Nature Communications, vol. 8, no. 1, 2149. https://doi.org/10.1038/s41467-017-01742-7
Fang, Jennifer S. ; Coon, Brian G. ; Gillis, Noelle ; Chen, Zehua ; Qiu, Jingyao ; Chittenden, Thomas W. ; Burt, Janis M ; Schwartz, Martin A. ; Hirschi, Karen K. / Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification. In: Nature Communications. 2017 ; Vol. 8, No. 1.
@article{a5fda39d6b15426e95b94c173f6e1bc2,
title = "Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification",
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.",
author = "Fang, {Jennifer S.} and Coon, {Brian G.} and Noelle Gillis and Zehua Chen and Jingyao Qiu and Chittenden, {Thomas W.} and Burt, {Janis M} and Schwartz, {Martin A.} and Hirschi, {Karen K.}",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41467-017-01742-7",
language = "English (US)",
volume = "8",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification

AU - Fang, Jennifer S.

AU - Coon, Brian G.

AU - Gillis, Noelle

AU - Chen, Zehua

AU - Qiu, Jingyao

AU - Chittenden, Thomas W.

AU - Burt, Janis M

AU - Schwartz, Martin A.

AU - Hirschi, Karen K.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85038223461&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038223461&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-01742-7

DO - 10.1038/s41467-017-01742-7

M3 - Article

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2149

ER -