ZFIN ID: ZDB-PUB-160602-18
TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis
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.
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:
  • Animals
  • Atherosclerosis/metabolism*
  • Atherosclerosis/pathology
  • Blood Flow Velocity/physiology*
  • Cell Movement/physiology
  • Cell Proliferation/physiology
  • Cells, Cultured
  • Endothelial Cells/metabolism
  • Endothelial Cells/pathology
  • Endothelium, Vascular/metabolism*
  • Endothelium, Vascular/pathology
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Human Umbilical Vein Endothelial Cells/pathology
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nuclear Proteins/biosynthesis*
  • Swine
  • Twist-Related Protein 1/biosynthesis*
  • Zebrafish
PubMed: 27245171 Full text @ Circ. Res.
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.