title: Cyclic strain increases protease-activated receptor-1 expression in vascular smooth muscle cells.
abstract: Cyclic strain regulates many vascular smooth muscle cell (VSMC) functions through changing gene expression. This study investigated the effects of cyclic strain on protease-activated receptor-1 (PAR-1) expression in VSMCs and the possible signaling pathways involved, on the basis of the hypothesis that cyclic strain would enhance PAR-1 expression, reflecting increased thrombin activity. Uniaxial cyclic strain (1 Hz, 20%) of cells cultured on elastic membranes induced a 2-fold increase in both PAR-1 mRNA and protein levels. Functional activity of PAR-1, as assessed by cell proliferation in response to thrombin, was also increased by cyclic strain. In addition, treatment of cells with antioxidants or an NADPH oxidase inhibitor blocked strain-induced PAR-1 expression. Preincubation of cells with protein kinase inhibitors (staurosporine or Ro 31-8220) enhanced strain-increased PAR-1 expression, whereas inhibitors of NO synthase, tyrosine kinase, and mitogen-activated protein kinases had no effect. Cyclic strain in the presence of basic fibroblast growth factor induced PAR-1 mRNA levels beyond the effect of cyclic strain alone, whereas no additive effect was observed between cyclic strain and platelet-derived growth factor-AB. Our findings that cyclic strain upregulates PAR-1 mRNA expression but that shear stress downregulates this gene in VSMCs provide an opportunity to elucidate signaling differences by which VSMCs respond to different mechanical forces.
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: S R
authors.initials: SR
authors.lastname: Frye
authors.forename: S G
authors.initials: SG
authors.lastname: Eskin
authors.forename: C
authors.initials: C
authors.lastname: Patterson
authors.forename: M S
authors.initials: MS
authors.lastname: Runge
authors.forename: L V
authors.initials: LV
authors.lastname: McIntire
mesh_terms: D001011:Aorta / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000502:physiology; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000096:biosynthesis* / Q000235:genetics; D013314:Stress, Mechanical; D013917:Thrombin / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: D004791:Enzyme Inhibitors; D006133:Growth Substances; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D019001:Nitric Oxide Synthase; D011494:Protein Kinases; D013917:Thrombin