en
Scientific article
English

Regulation of contractile signaling and matrix remodeling by T-cadherin in vascular smooth muscle cells: constitutive and insulin-dependent effects

Published inCellular signalling, vol. 26, no. 9, p. 1897-1908
Publication date2014
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.

Funding
  • Swiss National Science Foundation - 310030_132469
  • Autre - Stiftung für Herz- und Kreislaufkrankheiten; SwissLife Jubilaümsstiftung; Stiftung der Diabetes-Gesellschaft Region Base
Citation (ISO format)
FRISMANTIENE, Agne et al. 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, n° 9, p. 1897–1908. doi: 10.1016/j.cellsig.2014.05.001
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ISSN of the journal0898-6568
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