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TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis

Title: TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis
Authors: Mahmoud, MM
Kim, HR
Xing, R
Hsiao, S
Mammoto, A
Chen, J
Serbanovic-Canic, J
Feng, S
Bowden, NP
Maguire, R
Ariaans, M
Francis, SE
Weinberg, PD
Van der Heiden, K
Jones, EA
Chico, TJA
Ridger, V
Evans, PC
Item Type: Journal Article
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.
Issue Date: 31-May-2016
Date of Acceptance: 27-May-2016
URI: http://hdl.handle.net/10044/1/56514
DOI: https://dx.doi.org/10.1161/CIRCRESAHA.116.308870
ISSN: 0009-7330
Publisher: American Heart Association
Start Page: 450
End Page: 462
Journal / Book Title: Circulation Research
Volume: 119
Issue: 3
Copyright Statement: © 2016 The Authors. Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: PG/09/088/28058
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Hematology
Peripheral Vascular Disease
Cardiovascular System & Cardiology
atherosclerosis
cholesterol
gastrulation
obesity
transcription factors
FLUID SHEAR-STRESS
MESENCHYMAL TRANSITION
DISTURBED FLOW
TRANSCRIPTION FACTOR
DROSOPHILA EMBRYOS
TUMOR-METASTASIS
CELL-CYCLE
IN-VIVO
EXPRESSION
PATHWAY
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
1103 Clinical Sciences
1102 Cardiovascular Medicine And Haematology
Cardiovascular System & Hematology
Publication Status: Published
Appears in Collections:Faculty of Engineering
Bioengineering



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