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

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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.

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

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All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Frismantiene, A., Pfaff, D., Frachet, A., Coen, M., Joshi, M. B., Maslova, K., Bochaton-Piallat, M. L., Erne, P., Resink, T. J., & 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, 26(9), 1897-1908. https://doi.org/10.1016/j.cellsig.2014.05.001