title: Regulation of contractile signaling and matrix remodeling by T-cadherin in vascular smooth muscle cells: constitutive and insulin-dependent effects.
abstract: Expression of GPI-anchored T-cadherin (T-cad) on vascular smooth muscle cells (VSMC) is elevated in vascular disorders such as atherosclerosis and restenosis which are associated with insulin resistance. Functions for T-cad and signal transduction pathway utilization by T-cad in VSMC are unknown. The present study examines the consequences of altered T-cad expression on VSMC for constitutive and insulin-induced Akt/mTOR axis signaling and contractile competence. Using viral vectors rat (WKY and SHR) and human aortic VSMCs were variously transduced with respect to T-cad-overexpression (Tcad+-VSMC) or T-cad-deficiency (shT-VSMC) and compared with their respective control transductants (E-VSMC or shC-VSMC). Tcad+-VSMC exhibited elevated constitutive levels of phosphorylated Akt(ser473), GSK3β(ser9), S6RP(ser235/236) and IRS-1(ser636/639). Total IRS-1 levels were reduced. Contractile machinery was constitutively altered in a manner indicative of reduced intrinsic contractile competence, namely decreased phosphorylation of MYPT1(thr696 or thr853) and MLC20(thr18/ser19), reduced RhoA activity and increased iNOS expression. Tcad+-VSMC-populated collagen lattices exhibited greater compaction which was due to increased collagen fibril packing/reorganization. T-cad+-VSMC exhibited a state of insulin insensitivity as evidenced by attenuation of the ability of insulin to stimulate Akt/mTOR axis signaling, phosphorylation of MLC20 and MYPT1, compaction of free-floating lattices and collagen fibril reorganization in unreleased lattices. The effects of T-cad-deficiency on constitutive characteristics and insulin responsiveness of VSMC were opposite to those of T-cad-overexpression. The study reveals novel cadherin-based modalities to modulate VSMC sensitivity to insulin through Akt/mTOR axis signaling as well as vascular function and tissue architecture through the effects on contractile competence and organization of extracellular matrix.
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, University Hospital of Basel and University of Basel, Basel, Switzerland.
authors.forename: Agne
authors.initials: A
authors.lastname: Frismantiene
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, University Hospital of Basel and University of Basel, Basel, Switzerland.
authors.forename: Dennis
authors.initials: D
authors.lastname: Pfaff
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, University Hospital of Basel and University of Basel, Basel, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Frachet
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Faculty of Medicine, Switzerland.
authors.forename: Matteo
authors.initials: M
authors.lastname: Coen
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, University Hospital of Basel and University of Basel, Basel, Switzerland.
authors.forename: Manjunath B
authors.initials: MB
authors.lastname: Joshi
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, University Hospital of Basel and University of Basel, Basel, Switzerland; Hirslanden Klinik St Anna, Luzern, Switzerland.
authors.forename: Kseniya
authors.initials: K
authors.lastname: Maslova
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Faculty of Medicine, Switzerland.
authors.forename: Marie-Luce
authors.initials: ML
authors.lastname: Bochaton-Piallat
authors.affiliation: Hirslanden Klinik St Anna, Luzern, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Erne
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, University Hospital of Basel 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, University Hospital of Basel and University of Basel, Basel, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Philippova
mesh_terms: D000818:Animals; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D018994:Myosin Light Chains / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015820:Cadherins; C099972:H-cadherin; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D018994:Myosin Light Chains; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: Insulin resistance; Remodeling; Signal transduction; T-cadherin; Vascular smooth muscle cells