title: Arterial wall stress controls NFAT5 activity in vascular smooth muscle cells.
abstract: BACKGROUND
  Nuclear factor of activated T-cells 5 (NFAT5) has recently been described to control the phenotype of vascular smooth muscle cells (VSMCs). Although an increase in wall stress or stretch (eg, elicited by hypertension) is a prototypic determinant of VSMC activation, the impact of this biomechanical force on the activity of NFAT5 is unknown. This study intended to reveal the function of NFAT5 and to explore potential signal transduction pathways leading to its activation in stretch-stimulated VSMCs.
  
  
  RESULTS
  Human arterial VSMCs were exposed to biomechanical stretch and subjected to immunofluorescence and protein-biochemical analyses. Stretch promoted the translocation of NFAT5 to the nucleus within 24 hours. While the protein abundance of NFAT5 was regulated through activation of c-Jun N-terminal kinase under these conditions, its translocation required prior activation of palmitoyltransferases. DNA microarray and ChiP analyses identified the matrix molecule tenascin-C as a prominent transcriptional target of NFAT5 under these conditions that stimulates migration of VSMCs. Analyses of isolated mouse femoral arteries exposed to hypertensive perfusion conditions verified that NFAT5 translocation to the nucleus is followed by an increase in tenascin-C abundance in the vessel wall.
  
  
  CONCLUSIONS
  Collectively, our data suggest that biomechanical stretch is sufficient to activate NFAT5 both in native and cultured VSMCs where it regulates the expression of tenascin-C. This may contribute to an improved migratory activity of VSMCs and thus promote maladaptive vascular remodeling processes such as hypertension-induced arterial stiffening.
authors.affiliation: Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Scherer
authors.forename: Larissa
authors.initials: L
authors.lastname: Pfisterer
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Wagner
authors.forename: Maren
authors.initials: M
authors.lastname: Hödebeck
authors.forename: Marco
authors.initials: M
authors.lastname: Cattaruzza
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.forename: Thomas
authors.initials: T
authors.lastname: Korff
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D062186:Arterial Pressure; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005263:Femoral Artery / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D034622:RNA Interference; D013314:Stress, Mechanical; D019063:Tenascin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C118125:NFAT5 protein, human; C492200:Nfat5 protein, mouse; D019063:Tenascin; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases
keywords: NFAT5; hypertension; tenascin‐C; vascular smooth muscle cells; wall stress