Faculty Collaboration Database

TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis. Circ Res 2016 Jul 22;119(3):450-62

Date

06/02/2016

Pubmed ID

27245171

Pubmed Central ID

PMC4959828

DOI

10.1161/CIRCRESAHA.116.308870

Scopus ID

2-s2.0-84973327121 (requires institutional sign-in at Scopus site)   107 Citations

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.

Author List

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 TJ, Ridger V, Evans PC

Author

Akiko Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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