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Arterioscler Thromb Vasc Biol. 2019 Feb;39(2):250-262. doi: 10.1161/ATVBAHA.118.311830.

TCF7L2 (Transcription Factor 7-Like 2) Regulation of GATA6 (GATA-Binding Protein 6)-Dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia.

Author information

1
From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT.
2
Department of Pathology (A.A.), Yale School of Medicine, New Haven, CT.
3
Department of Surgery (A.G.), Yale School of Medicine, New Haven, CT.
4
Department of Human Genetics, University of Chicago, IL (M.N.).
5
Department of Genetics (A.M.), Yale School of Medicine, New Haven, CT.

Abstract

Objective- TCF7L2 (transcription factor 7-like 2) is a Wnt-regulated transcription factor that maintains stemness and promotes proliferation in embryonic tissues and adult stem cells. Mice with a coronary artery disease-linked mutation in Wnt-coreceptor LRP6 (LDL receptor-related protein 6) exhibit vascular smooth muscle cell dedifferentiation and obstructive coronary artery disease, which are paradoxically associated with reduced TCF7L2 expression. We conducted a comprehensive study to explore the role of TCF7L2 in vascular smooth muscle cell differentiation and protection against intimal hyperplasia. Approach and Results- Using multiple mouse models, we demonstrate here that TCF7L2 promotes differentiation and inhibits proliferation of vascular smooth muscle cells. TCF7L2 accomplishes these effects by stabilization of GATA6 (GATA-binding protein 6) and upregulation of SM-MHC (smooth muscle cell myosin heavy chain) and cell cycle inhibitors. Accordingly, TCF7L2 haploinsufficient mice exhibited increased susceptibility to injury-induced hyperplasia, while mice overexpressing TCF7L2 were protected against injury-induced intimal hyperplasia compared with wild-type littermates. Consequently, the overexpression of TCF7L2 in LRP6 mutant mice rescued the injury-induced intimal hyperplasia. Conclusions- Our novel findings imply cell type-specific functional role of TCF7L2 and provide critical insight into mechanisms underlying the pathogenesis of intimal hyperplasia.

KEYWORDS:

cell cycle; cell differentiation; hyperplasia; mice, laboratory; mutation

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