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Glycogen synthase kinase 3 beta positively regulates Notch signaling in vascular smooth muscle cells: role in cell proliferation and survival

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Abstract

The role of glycogen synthase kinase 3 beta (GSK-3β) in modulating Notch control of vascular smooth muscle cell (vSMC) growth (proliferation and apoptosis) was examined in vitro under varying conditions of cyclic strain and validated in vivo following changes in medial tension and stress. Modulation of GSK-3β in vSMC following ectopic expression of constitutively active GSK-3β, siRNA knockdown and pharmacological inhibition with SB-216763 demonstrated that GSK-3β positively regulates Notch intracellular domain expression, CBF-1/RBP-Jκ transactivation and downstream target gene mRNA levels, while concomitantly promoting vSMC proliferation and inhibiting apoptosis. In contrast, inhibition of GSK-3β attenuated Notch signaling and decreased vSMC proliferation and survival. Exposure of vSMC to cyclic strain environments in vitro using both a Flexercell™ Tension system and a novel Sylgard™ phantom vessel following bare metal stent implantation revealed that cyclic strain inhibits GSK-3β activity independent of p42/p44 MAPK and p38 activation concomitant with reduced Notch signaling and decreased vSMC proliferation and survival. Exposure of vSMC to changes in medial strain microenvironments in vivo following carotid artery ligation revealed that enhanced GSK-3β activity was predominantly localized to medial and neointimal vSMC concomitant with increased Notch signaling, proliferating nuclear antigen and decreased Bax expression, respectively, as vascular remodeling progressed. GSK-3β is an important modulator of Notch signaling leading to altered vSMC cell growth where low strain/tension microenvironments prevail.

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Acknowledgments

This work was supported in part by grants from Science Foundation Ireland (PAC and CL) and the Health Research Board of Ireland (PAC) and by funds from the National Institutes of Health, (AA-12610 to E.M.R and K99HL095650 to D.M.) and the American Heart Association (Grant-in-Aid 0855865D to J.P.C).

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Authors and Affiliations

  1. Vascular Health Research Centre, Faculty of Science and Health, Dublin City University, Dublin 9, Ireland

    Shaunta Guha, Alberto Colombo, Caitríona Lally & Paul A. Cahill

  2. Department of Surgery, University of Rochester Medical Center, Rochester, NY, 14642, USA

    John P. Cullen, David Morrow & Eileen M. Redmond

  3. School of Mechanical and Manufacturing Engineering, Dublin City University, Dublin 9, Ireland

    Alberto Colombo & Caitríona Lally

  4. School of Biotechnology and the National Centre for Sensor Research, Dublin City University, Dublin 9, Ireland

    Dermot Walls

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  1. Shaunta Guha
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Correspondence to Paul A. Cahill.

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E.M. Redmond, P.A. Cahill contributed equally to the preparation of this work.

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Guha, S., Cullen, J.P., Morrow, D. et al. Glycogen synthase kinase 3 beta positively regulates Notch signaling in vascular smooth muscle cells: role in cell proliferation and survival. Basic Res Cardiol 106, 773–785 (2011). https://doi.org/10.1007/s00395-011-0189-5

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