title: Loss of the mechanotransducer zyxin promotes a synthetic phenotype of vascular smooth muscle cells.
abstract: BACKGROUND
  Exposure of vascular smooth muscle cells (VSMCs) to excessive cyclic stretch such as in hypertension causes a shift in their phenotype. The focal adhesion protein zyxin can transduce such biomechanical stimuli to the nucleus of both endothelial cells and VSMCs, albeit with different thresholds and kinetics. However, there is no distinct vascular phenotype in young zyxin-deficient mice, possibly due to functional redundancy among other gene products belonging to the zyxin family. Analyzing zyxin function in VSMCs at the cellular level might thus offer a better mechanistic insight. We aimed to characterize zyxin-dependent changes in gene expression in VSMCs exposed to biomechanical stretch and define the functional role of zyxin in controlling the resultant VSMC phenotype.
  
  
  RESULTS
  DNA microarray analysis was used to identify genes and pathways that were zyxin regulated in static and stretched human umbilical artery-derived and mouse aortic VSMCs. Zyxin-null VSMCs showed a remarkable shift to a growth-promoting, less apoptotic, promigratory and poorly contractile phenotype with ≈90% of the stretch-responsive genes being zyxin dependent. Interestingly, zyxin-null cells already seemed primed for such a synthetic phenotype, with mechanical stretch further accentuating it. This could be accounted for by higher RhoA activity and myocardin-related transcription factor-A mainly localized to the nucleus of zyxin-null VSMCs, and a condensed and localized accumulation of F-actin upon stretch.
  
  
  CONCLUSIONS
  At the cellular level, zyxin is a key regulator of stretch-induced gene expression. Loss of zyxin drives VSMCs toward a synthetic phenotype, a process further consolidated by exaggerated stretch.
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Germany (S.G., B.K., T.N., A.H.W., T.K.).
authors.forename: Subhajit
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Germany (S.G., B.K., T.N., A.H.W., T.K.).
authors.forename: Branislav
authors.initials: B
authors.lastname: Kollar
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Germany (S.G., B.K., T.N., A.H.W., T.K.).
authors.forename: Taslima
authors.initials: T
authors.lastname: Nahar
authors.affiliation: Department of Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX (S.S.B.).
authors.forename: Sahana
authors.initials: S
authors.lastname: Suresh Babu
authors.affiliation: Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland (A.W.).
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wojtowicz
authors.affiliation: ZMF, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (C.S., N.G.).
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.affiliation: ZMF, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (C.S., N.G.).
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Germany (S.G., B.K., T.N., A.H.W., T.K.).
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Wagner
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Germany (S.G., B.K., T.N., A.H.W., T.K.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Korff
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg and Deutsches Zentrum Für Herz-Kreislauf-Forschung E.V. (DZHK), Partner site Heidelberg/Mannheim, Germany (M.H.).
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
mesh_terms: D000086:Acetazolamide; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001696:Biomechanical Phenomena / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000502:physiology; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D014469:Umbilical Arteries / Q000502:physiology; D060589:Zyxin / Q000502:physiology*
chemical_list: C092842:ZYX protein, human; C498285:Zyx protein, mouse; D060589:Zyxin; D000086:Acetazolamide
keywords: gene expression; hypertension; remodeling; vascular smooth muscle cells; zyxin