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
-
- Mice, Knockout
- Swine
- Atherosclerosis/metabolism*
- Atherosclerosis/pathology
- Zebrafish
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Blood Flow Velocity/physiology*
- Animals
- Cells, Cultured
- Cell Movement/physiology
- Mice, Transgenic
- Humans
- Cell Proliferation/physiology
- Human Umbilical Vein Endothelial Cells/metabolism
- Human Umbilical Vein Endothelial Cells/pathology
- Endothelium, Vascular/metabolism*
- Endothelium, Vascular/pathology
- Mice
- Male
- Nuclear Proteins/biosynthesis*
- Twist-Related Protein 1/biosynthesis*
- PubMed
- 27245171 Full text @ Circ. Res.
Citation
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. (2016) TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis. Circulation research. 119(3):450-62.
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 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 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.
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 as well as development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping