α8 Integrin overexpression in de-differentiated vascular smooth muscle cells attenuates migratory activity and restores the characteristics of the differentiated phenotype

  • Ramin Zargham
    Institut de recherches cliniques de Montréal, Université de Montréal and Experimental Medicine Department, McGill University, 110 Avenue des Pins ouest Montréal, Montréal, Quebec, Canada H2W 1R7
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  • Rhian M. Touyz
    Kidney Research Center, Ottawa Health Research Institute, University of Ottawa, Ontario, Canada
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  • Gaétan Thibault
    Corresponding author. Tel.: +1 514 987 5613; fax: +1 514 987 5585.
    Institut de recherches cliniques de Montréal, Université de Montréal and Experimental Medicine Department, McGill University, 110 Avenue des Pins ouest Montréal, Montréal, Quebec, Canada H2W 1R7
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      Loss of the differentiated (contractile) phenotype of vascular smooth muscle cells (VSMCs) heightens their migratory activity. Integrins, as the main integrators of cell-extracellular matrix, regulate different aspects of cell behavior including migration and differentiation. α8β1 Integrin being expressed in cell types with contractile abilities is downregulated during VSMC phenotype modulation. In this report the ability of α8β1 integrin to induce the characteristics of the contractile phenotype as well as suppression of VSMC migratory activity was investigated. Forced expression of α8 integrin in passage-5 rat VSMCs resulted in lower migratory activity. Western blot and immunoconfocal studies revealed that α8 integrin overexpression was associated with the reappearance of VSMC contractile hallmarks including upregulation of contractile markers, assembly of stress fibres, and increased number of focal adhesions. α8 Integrin overexpression in fibroblast-like Rat1 cells also induced SMC-like characteristics. α8 Integrin-induced reappearance of the contractile hallmarks in de-differentiated VSMCs was impaired by RhoA inhibitors. These results provide evidences that α8 integrin overexpression may assist phenotype-modulated VSMCs to revert to the contractile phenotype possibly via RhoA signaling pathway. Our findings suggest a dynamic role for α8β1 integrin to induce contractile phenotype as well as suppression of VSMC migration, a key player during arterial stenosis.


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        • Schoenwaelder S.M.
        • Burridge K.
        Bidirectional signaling between the cytoskeleton and integrins.
        Curr Opin Cell Biol. 1999; 11: 274-286
        • Opazo Saez A.
        • Zhang W.
        • Wu Y.
        • et al.
        Tension development during contractile stimulation of smooth muscle requires recruitment of paxillin and vinculin to the membrane.
        Am J Physiol Cell Physiol. 2004; 286: C433-C447
        • Peyton S.R.
        • Putnam A.J.
        Extracellular matrix rigidity governs smooth muscle cell motility in a biphasic fashion.
        J Cell Physiol. 2005; 204: 198-209
        • Critchley D.R.
        Cytoskeletal proteins talin and vinculin in integrin-mediated adhesion.
        Biochem Soc Trans. 2004; 32: 831-836
        • Moiseeva E.P.
        Adhesion receptors of vascular smooth muscle cells and their functions.
        Cardiovasc Res. 2001; 52: 372-386
        • Zargham R.
        • Thibault G.
        α8β1 Integrin expression in the rat carotid artery: involvement in smooth muscle cell migration and neointima formation.
        Cardiovasc Res. 2005; 65: 813-822
        • Mack C.P.
        • Somlyo A.V.
        • Hautmann M.
        • Somlyo A.P.
        • Owens G.K.
        Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization.
        J Biol Chem. 2001; 276: 341-347
        • Zargham R.
        • Thibault G.
        α8 Integrin expression is required for maintenance of the smooth muscle cell differentiated phenotype.
        Cardiovasc Res. 2006; 71: 170-178
        • Owens G.K.
        Regulation of differentiation of vascular smooth muscle cells.
        Physiol Rev. 1995; 75: 487-517
        • Sobue K.
        • Hayashi K.
        • Nishida W.
        Expressional regulation of smooth muscle cell-specific genes in association with phenotypic modulation.
        Mol Cell Biochem. 1999; 190: 105-118
        • Burridge K.
        • Chrzanowska-Wodnicka M.
        Focal adhesions, contractility, and signaling.
        Annu Rev Cell Dev Biol. 1996; 12: 463-518
        • Worth N.F.
        • Rolfe B.E.
        • Song J.
        • Campbell G.R.
        Vascular smooth muscle cell phenotypic modulation in culture is associated with reorganisation of contractile and cytoskeletal proteins.
        Cell Motil Cytoskeleton. 2001; 49: 130-145
        • Goffin J.M.
        • Pittet P.
        • Csucs G.
        • et al.
        Focal adhesion size controls tension-dependent recruitment of alpha-smooth muscle actin to stress fibers.
        J Cell Biol. 2006; 172: 259-268
        • Numaguchi K.
        • Eguchi S.
        • Yamakawa T.
        • Motley E.D.
        • Inagami T.
        Mechanotransduction of rat aortic vascular smooth muscle cells requires RhoA and intact actin filaments.
        Circ Res. 1999; 85: 5-11
        • Chrzanowska-Wodnicka M.
        • Burridge K.
        Rho-stimulated contractility drives the formation of stress fibers and focal adhesions.
        J Cell Biol. 1996; 133: 1403-1415
        • Weber D.S.
        • Webb R.C.
        Enhanced relaxation to the rho-kinase inhibitor Y-27632 in mesenteric arteries from mineralocorticoid hypertensive rats.
        Pharmacology. 2001; 63: 129-133
        • Parsons J.T.
        • Martin K.H.
        • Slack J.K.
        • Taylor J.M.
        • Weed S.A.
        Focal adhesion kinase: a regulator of focal adhesion dynamics and cell movement.
        Oncogene. 2000; 19: 5606-5613
        • Burridge K.
        Crosstalk between Rac and Rho.
        Science. 1999; 283: 2028-2029
        • Franck Z.
        • Footer M.
        • Bretscher A.
        Microinjection of villin into cultured cells induces rapid and long-lasting changes in cell morphology but does not inhibit cytokinesis, cell motility, or membrane ruffling.
        J Cell Biol. 1990; 111: 2475-2485
        • Rodriguez Fernandez J.L.
        • Geiger B.
        • Salomon D.
        • Ben-Ze’ev A.
        Overexpression of vinculin suppresses cell motility in BALB/c 3T3 cells.
        Cell Motil Cytoskeleton. 1992; 22: 127-134
        • Miralles F.
        • Posern G.
        • Zaromytidou A.I.
        • Treisman R.
        Actin dynamics control SRF activity by regulation of its coactivator MAL.
        Cell. 2003; 113: 329-342
        • Hao H.
        • Gabbiani G.
        • Bochaton-Piallat M.L.
        Arterial smooth muscle cell heterogeneity: implications for atherosclerosis and restenosis development.
        Arterioscler Thromb Vasc Biol. 2003; 23: 1510-1520
        • Miano J.M.
        • Cserjesi P.
        • Ligon K.L.
        • Periasamy M.
        • Olson E.N.
        Smooth muscle myosin heavy chain exclusively marks the smooth muscle lineage during mouse embryogenesis.
        Circ Res. 1994; 75: 803-812
        • Tomasek J.J.
        • Gabbiani G.
        • Hinz B.
        • Chaponnier C.
        • Brown R.A.
        Myofibroblasts and mechano-regulation of connective tissue remodelling.
        Nat Rev Mol Cell Biol. 2002; 3: 349-363
        • Perez-Montiel M.D.
        • Plaza J.A.
        • Dominguez-Malagon H.
        • Suster S.
        Differential expression of smooth muscle myosin, smooth muscle actin, h-caldesmon, and calponin in the diagnosis of myofibroblastic and smooth muscle lesions of skin and soft tissue.
        Am J Dermatopathol. 2006; 28: 105-111
        • Blindt R.
        • Krott N.
        • Hanrath P.
        • et al.
        Expression patterns of integrins on quiescent and invasive smooth muscle cells and impact on cell locomotion.
        J Mol Cell Cardiol. 2002; 34: 1633-1644
        • Kappert K.
        • Blaschke F.
        • Meehan W.P.
        • et al.
        Integrins alphavbeta3 and alphavbeta5 mediate VSMC migration and are elevated during neointima formation in the rat aorta.
        Basic Res Cardiol. 2001; 96: 42-49
        • Schnapp L.M.
        • Hatch N.
        • Ramos D.M.
        • et al.
        The human integrin α8β1 functions as a receptor for tenascin, fibronectin, and vitronectin.
        J Biol Chem. 1995; 270: 23196-23202
        • Muller U.
        • Bossy B.
        • Venstrom K.
        • Reichardt L.F.
        Integrin alpha 8 beta 1 promotes attachment, cell spreading, and neurite outgrowth on fibronectin.
        Mol Biol Cell. 1995; 6: 433-448
        • Bieritz B.
        • Spessotto P.
        • Colombatti A.
        • et al.
        Role of α8 integrin in mesangial cell adhesion, migration, and proliferation.
        Kidney Int. 2003; 64: 119-127