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Circ Res. 2016 Jul 22;119(3):450-62. doi: 10.1161/CIRCRESAHA.116.308870. Epub 2016 May 31.

TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis.

Author information

1
From the Department of Infection, Immunity and Cardiovascular Disease, INSIGNEO Institute for In Silico Medicine, and the Bateson Centre, University of Sheffield, Sheffield, United Kingdom (M.M.M., H.R.K., S.H., J.S.-C., S.F., N.P.B., R.M., M.A., S.E.F., T.J.A.C., V.R., P.C.E.); ERASMUS MC, Rotterdam, The Netherlands (R.X., K.v.d.H.); Vascular Biology Program, Department of Surgery (A.M.) and Department of Ophthalmology (J.C.), Boston Children's Hospital, Harvard Medical School, MA; Department of Bioengineering, Imperial College London, London, United Kingdom (P.D.W.); and Department of Cardiovascular Science, Katholieke Universiteit Leuven, Leuven, Belgium (E.A.J.).
2
From the Department of Infection, Immunity and Cardiovascular Disease, INSIGNEO Institute for In Silico Medicine, and the Bateson Centre, University of Sheffield, Sheffield, United Kingdom (M.M.M., H.R.K., S.H., J.S.-C., S.F., N.P.B., R.M., M.A., S.E.F., T.J.A.C., V.R., P.C.E.); ERASMUS MC, Rotterdam, The Netherlands (R.X., K.v.d.H.); Vascular Biology Program, Department of Surgery (A.M.) and Department of Ophthalmology (J.C.), Boston Children's Hospital, Harvard Medical School, MA; Department of Bioengineering, Imperial College London, London, United Kingdom (P.D.W.); and Department of Cardiovascular Science, Katholieke Universiteit Leuven, Leuven, Belgium (E.A.J.). paul.evans@sheffield.ac.uk.

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.

KEYWORDS:

atherosclerosis; cholesterol; gastrulation; obesity; transcription factors

PMID:
27245171
PMCID:
PMC4959828
DOI:
10.1161/CIRCRESAHA.116.308870
[Indexed for MEDLINE]
Free PMC Article

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