title: Nox4-dependent activation of cofilin mediates VSMC reorientation in response to cyclic stretching.
abstract: Vascular smooth muscle cells (VSMCs) are subjected to various types of mechanical forces within the vessel wall. Although it is known that VSMCs undergo cell body reorientation in response to mechanical stimulation, how this mechanical stretch is transduced within the cell into biochemical signals causing cytoskeleton reorganization remains unclear. Cofilin, a protein that controls actin dynamics, is activated by Slingshot phosphatase-dependent serine 3 dephosphorylation by redox-dependent mechanisms. Nox4 is a main source of reactive oxygen species (ROS) in the vessel wall that localizes in association with the cytoskeleton. Therefore, we hypothesize that Nox4 mediates redox-dependent activation of cofilin, which is required for cytoskeletal reorganization and cell reorientation after mechanical stimulation. In this study, we found that mechanical stretch stimulates ROS production in VSMCs and that the signaling that leads to cell reorientation requires hydrogen peroxide but not superoxide. Indeed, mechanical stretch induces cofilin activation and stretch-induced cytoskeletal reorganization, and cell reorientation is inhibited in cells where cofilin activity has been downregulated. Importantly, Nox4-deficient cells fail to activate cofilin and to undergo cell reorientation, a phenotype rescued by the expression of a constitutively active cofilin mutant. Our results demonstrate that in VSMCs mechanical stimulation activates cofilin by a Nox4-dependent mechanism and that this pathway is required for cytoskeleton reorganization and cell reorientation.
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University, city Atlanta, state, GA zip 30322, country USA.
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Montenegro
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University, city Atlanta, state, GA zip 30322, country USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Valdivia
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University, city Atlanta, state, GA zip 30322, country USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Smolensky
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University, city Atlanta, state, GA zip 30322, country USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Verma
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University, city Atlanta, state, GA zip 30322, country USA.
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University, city Atlanta, state, GA zip 30322, country USA. Electronic address: asanmartin@emory.edu.
authors.forename: Alejandra
authors.initials: A
authors.lastname: San Martín
mesh_terms: D002478:Cells, Cultured; D051338:Cofilin 1 / Q000378:metabolism*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D013314:Stress, Mechanical
chemical_list: D051338:Cofilin 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human
keywords: Cofilin; Free radicals; Human vascular smooth muscle cells; Hydrogen peroxide; Nox4; Slingshot-1