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TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis

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Author(s)

  • Marwa M Mahmoud
  • Hyejeong Rosemary Kim
  • Rouyu Xing
  • Sarah Hsiao
  • Akiko Mammoto
  • Jing Chen
  • Jovana Serbanovic-Canic
  • Shuang Feng
  • Neil P Bowden
  • Richard Maguire
  • Markus Ariaans
  • Sheila E Francis
  • Peter D Weinberg
  • Kim van der Heiden
  • Elizabeth A Jones
  • Timothy J A Chico
  • Victoria Ridger
  • Paul C Evans

Department/unit(s)

Publication details

JournalCirculation Research
DateAccepted/In press - 22 May 2016
DateE-pub ahead of print - 31 May 2016
DatePublished (current) - 22 Jul 2016
Issue number3
Volume119
Number of pages13
Pages (from-to)450-62
Early online date31/05/16
Original languageEnglish

Abstract

RATIONALE: 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.

OBJECTIVE: To investigate whether TWIST regulates endothelial responses to shear stress during vascular dysfunction and atherosclerosis and compare TWIST function in vascular development and disease.

METHODS AND RESULTS: 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 quantitative polymerase chain reaction 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.

CONCLUSIONS: 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 and development.

Bibliographical note

© 2016 The Authors

    Research areas

  • Animals, Atherosclerosis, Blood Flow Velocity, Cell Movement, Cell Proliferation, Cells, Cultured, Endothelial Cells, Endothelium, Vascular, Human Umbilical Vein Endothelial Cells, Humans, Male, Mice, Mice, Knockout, Mice, Transgenic, Nuclear Proteins, Swine, Twist-Related Protein 1, Zebrafish, Journal Article

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