title: T-cadherin promotes vascular smooth muscle cell dedifferentiation via a GSK3β-inactivation dependent mechanism.
abstract: Participation of the cadherin superfamily of adhesion molecules in smooth muscle cell (SMC) phenotype modulation is poorly understood. Immunohistochemical analyses of arterial lesions indirectly suggest upregulated expression of atypical glycosylphosphatidylinositol-anchored T-cadherin on vascular SMCs as a molecular indicator of the dedifferentiated/proliferative phenotype. This study investigated the role of T-cadherin in SMC phenotypic modulation. Morphological, molecular and functional SMC-signature characteristics of rat, porcine and human arterial SMCs stably transduced with respect to T-cadherin upregulation (Tcad+) or T-cadherin-deficiency (shTcad) were compared with their respective control transductants (E-SMCs or shC-SMCs). Tcad+-SMCs displayed several characteristics of the dedifferentiated phenotype including loss of spindle morphology, reduced/disorganized stress fiber formation, decay of SMC-differentiation markers (smooth muscle α-actin, smooth muscle myosin heavy chain, h-caldesmon), gain of SMC-dedifferentiation marker calmodulin, reduced levels of myocardin, nuclear-to-cytoplasmic redistribution of the myocardin related transcription factors MRTFA/B and increased proliferative and migratory capacities. T-cadherin depletion enforced features of the differentiated SMC phenotype. PI3K/Akt is a major signal pathway utilized by T-cadherin in SMCs and we investigated mTORC1/S6K1 and GSK3β axes as mediators of T-cadherin-induced dedifferentiation. Inhibition of mTORC1/S6K1 signalling by rapamycin suppressed proliferation in both E-SMCs and Tcad+-SMCs but failed to restore expression of contractile protein markers in Tcad+-SMCs. Ectopic adenoviral-mediated co-expression of constitutively active GSK3β mutant S9A in Tcad+-SMCs restored the morphological and molecular marker characteristics of differentiated SMCs and normalized rate of proliferation to that in control SMCs. In conclusion our study demonstrates that T-cadherin promotes acquisition of the dedifferentiated phenotype via a mechanism that is dependent on GSK3β inactivation.
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Agne
authors.initials: A
authors.lastname: Frismantiene
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Boris
authors.initials: B
authors.lastname: Dasen
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Dennis
authors.initials: D
authors.lastname: Pfaff
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Erne
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland. Electronic address: Therese-J.Resink@unibas.ch.
authors.forename: Therese J
authors.initials: TJ
authors.lastname: Resink
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Philippova
mesh_terms: D000818:Animals; D015820:Cadherins / Q000502:physiology*; D054337:Cell Dedifferentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000648:ultrastructure; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011921:Rats, Inbred WKY; D015398:Signal Transduction; D013552:Swine
chemical_list: D015820:Cadherins; C099972:H-cadherin; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: GSK3β; Phenotype modulation; SMC plasticity; T-cadherin; Vascular smooth muscle cells