Regulation of contractile signaling and matrix remodeling by T-cadherin in vascular smooth muscle cells

Constitutive and insulin-dependent effects

Agne Frismantiene, Dennis Pfaff, Audrey Frachet, Matteo Coen, Manjunath B. Joshi, Kseniya Maslova, Marie Luce Bochaton-Piallat, Paul Erne, Therese J. Resink, Maria Philippova

    Research output: Contribution to journalArticle

    9 Citations (Scopus)

    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 Aktser473, GSK3βser9, S6RPser235/236 and IRS-1ser636/639. Total IRS-1 levels were reduced. Contractile machinery was constitutively altered in a manner indicative of reduced intrinsic contractile competence, namely decreased phosphorylation of MYPT1thr696 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. •Signaling pathway utilization and functions for T-cad in VSMC were identified.

    Original languageEnglish
    Pages (from-to)1897-1908
    Number of pages12
    JournalCellular Signalling
    Volume26
    Issue number9
    DOIs
    Publication statusPublished - 2014

    Fingerprint

    Vascular Smooth Muscle
    Smooth Muscle Myocytes
    Insulin
    Mental Competency
    Collagen
    H-cadherin
    Blood Vessels
    Insulin Resistance
    Phosphorylation
    Aptitude
    Inbred WKY Rats
    Inbred SHR Rats
    Cadherins
    Extracellular Matrix
    Signal Transduction
    Atherosclerosis
    Organizations

    All Science Journal Classification (ASJC) codes

    • Cell Biology

    Cite this

    Frismantiene, Agne ; Pfaff, Dennis ; Frachet, Audrey ; Coen, Matteo ; Joshi, Manjunath B. ; Maslova, Kseniya ; Bochaton-Piallat, Marie Luce ; Erne, Paul ; Resink, Therese J. ; Philippova, Maria. / Regulation of contractile signaling and matrix remodeling by T-cadherin in vascular smooth muscle cells : Constitutive and insulin-dependent effects. In: Cellular Signalling. 2014 ; Vol. 26, No. 9. pp. 1897-1908.
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    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 Aktser473, GSK3βser9, S6RPser235/236 and IRS-1ser636/639. Total IRS-1 levels were reduced. Contractile machinery was constitutively altered in a manner indicative of reduced intrinsic contractile competence, namely decreased phosphorylation of MYPT1thr696 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. •Signaling pathway utilization and functions for T-cad in VSMC were identified.",
    author = "Agne Frismantiene and Dennis Pfaff and Audrey Frachet and Matteo Coen and Joshi, {Manjunath B.} and Kseniya Maslova and Bochaton-Piallat, {Marie Luce} and Paul Erne and Resink, {Therese J.} and Maria Philippova",
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    Frismantiene, A, Pfaff, D, Frachet, A, Coen, M, Joshi, MB, Maslova, K, Bochaton-Piallat, ML, Erne, P, Resink, TJ & Philippova, M 2014, 'Regulation of contractile signaling and matrix remodeling by T-cadherin in vascular smooth muscle cells: Constitutive and insulin-dependent effects', Cellular Signalling, vol. 26, no. 9, pp. 1897-1908. https://doi.org/10.1016/j.cellsig.2014.05.001

    Regulation of contractile signaling and matrix remodeling by T-cadherin in vascular smooth muscle cells : Constitutive and insulin-dependent effects. / Frismantiene, Agne; Pfaff, Dennis; Frachet, Audrey; Coen, Matteo; Joshi, Manjunath B.; Maslova, Kseniya; Bochaton-Piallat, Marie Luce; Erne, Paul; Resink, Therese J.; Philippova, Maria.

    In: Cellular Signalling, Vol. 26, No. 9, 2014, p. 1897-1908.

    Research output: Contribution to journalArticle

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    T2 - Constitutive and insulin-dependent effects

    AU - Frismantiene, Agne

    AU - Pfaff, Dennis

    AU - Frachet, Audrey

    AU - Coen, Matteo

    AU - Joshi, Manjunath B.

    AU - Maslova, Kseniya

    AU - Bochaton-Piallat, Marie Luce

    AU - Erne, Paul

    AU - Resink, Therese J.

    AU - Philippova, Maria

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    N2 - 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 Aktser473, GSK3βser9, S6RPser235/236 and IRS-1ser636/639. Total IRS-1 levels were reduced. Contractile machinery was constitutively altered in a manner indicative of reduced intrinsic contractile competence, namely decreased phosphorylation of MYPT1thr696 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. •Signaling pathway utilization and functions for T-cad in VSMC were identified.

    AB - 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 Aktser473, GSK3βser9, S6RPser235/236 and IRS-1ser636/639. Total IRS-1 levels were reduced. Contractile machinery was constitutively altered in a manner indicative of reduced intrinsic contractile competence, namely decreased phosphorylation of MYPT1thr696 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. •Signaling pathway utilization and functions for T-cad in VSMC were identified.

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