PUBLICATION

TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis

Authors
Mahmoud, M., Kim, H.R., Xing, R., Hsiao, S., Mammmoto, A., Chen, J., Serbanovic-Canic, J., Feng, S., Bowden, N.P., Maguire, R., Ariaans, M., Francis, S., Weinberg, P.D., Van der Heiden, K., Jones, E.A., Chico, T.J., Ridger, V.C., Evans, P.C.
ID
ZDB-PUB-160602-18
Date
2016
Source
Circulation research   119(3): 450-62 (Journal)
Registered Authors
Chen, Jing, Chico, Tim J.
Keywords
TWIST, endothelial cell, shear stress, transcription factors
MeSH Terms
  • Male
  • Humans
  • Mice, Transgenic
  • Nuclear Proteins/biosynthesis*
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Human Umbilical Vein Endothelial Cells/pathology
  • Cell Movement/physiology
  • Twist-Related Protein 1/biosynthesis*
  • Cells, Cultured
  • Cell Proliferation/physiology
  • Atherosclerosis/metabolism*
  • Atherosclerosis/pathology
  • Animals
  • Endothelial Cells/metabolism
  • Endothelial Cells/pathology
  • Mice
  • Zebrafish
  • Mice, Knockout
  • Blood Flow Velocity/physiology*
  • Swine
  • Endothelium, Vascular/metabolism*
  • Endothelium, Vascular/pathology
(all 22)
PubMed
27245171 Full text @ Circ. Res.
Abstract
Blood flow-induced shear stress controls endothelial cell (EC) physiology during atherosclerosis via transcriptional mechanisms that are incompletely understood. The mechanosensitive transcription factor TWIST is expressed during embryogenesis but its role in EC responses to shear stress and focal atherosclerosis is unknown.
Investigate whether TWIST regulates endothelial responses to shear stress during vascular dysfunction and atherosclerosis, and compare TWIST function in vascular development and disease.
The expression and function of TWIST1 was studied in EC in both developing vasculature and during the initiation of atherosclerosis. In zebrafish, twist was expressed in early embryonic vasculature where it promoted angiogenesis by inducing EC proliferation and migration. In adult porcine and murine arteries, TWIST1 was expressed preferentially at low shear stress regions as evidenced by qPCR and en face staining. Moreover, studies of experimental murine carotid arteries and cultured EC revealed that TWIST1 was induced by low shear stress via a GATA4-dependent transcriptional mechanism. Gene silencing in cultured EC and EC-specific genetic deletion in mice demonstrated that TWIST1 promoted atherosclerosis by inducing inflammation and enhancing EC proliferation associated with vascular leakiness.
TWIST expression promotes developmental angiogenesis by inducing EC proliferation and migration. In addition to its role in development, TWIST is expressed preferentially at low shear stress regions of adult arteries where it promotes atherosclerosis by inducing EC proliferation and inflammation. Thus pleiotropic functions of TWIST control vascular disease as well as development.
Genes / Markers
Figures
Figure Gallery (2 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
sh423
    Small Deletion
    ubs1TgTransgenic Insertion
      y1TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        twist1aMO1-twist1aMRPHLNO
        twist1bCRISPR1-twist1bCRISPR
        1 - 2 of 2
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        Fish
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        1 - 1 of 1
        Show
        Mapping
        No data available