title: Glycogen synthase kinase 3 beta positively regulates Notch signaling in vascular smooth muscle cells: role in cell proliferation and survival.
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.
authors.affiliation: Vascular Health Research Centre, Faculty of Science and Health, Dublin City University, Dublin 9, Ireland.
authors.forename: Shaunta
authors.initials: S
authors.lastname: Guha
authors.forename: John P
authors.initials: JP
authors.lastname: Cullen
authors.forename: David
authors.initials: D
authors.lastname: Morrow
authors.forename: Alberto
authors.initials: A
authors.lastname: Colombo
authors.forename: Caitríona
authors.initials: C
authors.lastname: Lally
authors.forename: Dermot
authors.initials: D
authors.lastname: Walls
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Redmond
authors.forename: Paul A
authors.initials: PA
authors.lastname: Cahill
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001696:Biomechanical Phenomena; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D058426:Neointima / Q000503:physiopathology; D051381:Rats; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051880:Receptors, Notch; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3