Basic Research in Cardiology

, 106:773 | Cite as

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

  • Shaunta Guha
  • John P. Cullen
  • David Morrow
  • Alberto Colombo
  • Caitríona Lally
  • Dermot Walls
  • Eileen M. Redmond
  • Paul A. Cahill
Original Contribution

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.

Keywords

Notch GSK-3β Vascular smooth muscle Cyclic strain Neointimal proliferation 

Notes

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).

Conflict of interest

None.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Shaunta Guha
    • 1
  • John P. Cullen
    • 2
  • David Morrow
    • 2
  • Alberto Colombo
    • 1
    • 3
  • Caitríona Lally
    • 1
    • 3
  • Dermot Walls
    • 4
  • Eileen M. Redmond
    • 2
  • Paul A. Cahill
    • 1
  1. 1.Vascular Health Research Centre, Faculty of Science and HealthDublin City UniversityDublin 9Ireland
  2. 2.Department of SurgeryUniversity of Rochester Medical CenterRochesterUSA
  3. 3.School of Mechanical and Manufacturing EngineeringDublin City UniversityDublin 9Ireland
  4. 4.School of Biotechnology and the National Centre for Sensor ResearchDublin City UniversityDublin 9Ireland

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