title: Shear stress preconditioning modulates endothelial susceptibility to circulating TNF-alpha and monocytic cell recruitment in a simplified model of arterial bifurcations.
abstract: OBJECTIVE
  Atherosclerotic plaque formation results from a combination of local shear stress patterns and inflammatory processes. This study investigated the endothelial response to shear stress in combination with the inflammatory cytokine TNF-alpha in a simplified model of arterial bifurcation.
  
  
  METHODS
  Human umbilical vein endothelial cells (ECs) were exposed to laminar or non-uniform shear stress in bifurcating flow-through slides, followed by stimulation with TNF-alpha. To study cell adhesion, ECs were perfused with medium containing THP-1 monocytic cells. Endothelial protein expression was determined by immunofluorescence.
  
  
  RESULTS
  Adhesion of monocytic cells to unstimulated ECs was nearly undetectable under laminar shear stress and was slightly increased under non-uniform shear stress. Exposure of ECs to non-uniform shear stress in combination with TNF-alpha induced a 12-fold increase in monocytic cell recruitment and a significant induction of endothelial E-selectin and VCAM-1 expression. Both these effects were prevented in ECs exposed to laminar shear stress. The significant differences in TNF-alpha-induced monocytic cell recruitment and adhesion molecule expression between laminar and non-uniform shear stress regions were abolished in the absence of shear stress preconditioning. Simvastatin (1 micromol/L) suppressed the non-uniform shear stress- and TNF-alpha-induced increase in monocytic cell adhesion by about 30% via inhibition of VCAM-1 expression. Resveratrol, the active component of red wine, inhibited the expression of both VCAM-1 and E-selectin, and reduced monocytic cell recruitment by 50% at 20 micromol/L.
  
  
  CONCLUSIONS
  Non-uniform shear stress induces endothelial susceptibility to circulating TNF-alpha and adhesion of monocytic cells. Interference with this process may inhibit inflammatory response in atherosclerosis-prone regions.
authors.affiliation: Laboratory of Molecular Cardiology, Medical Clinic 2, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany. Iwona_Cicha@yahoo.com
authors.forename: Iwona
authors.initials: I
authors.lastname: Cicha
authors.forename: Kamen
authors.initials: K
authors.lastname: Beronov
authors.forename: Efrain Lopez
authors.initials: EL
authors.lastname: Ramirez
authors.forename: Katharina
authors.initials: K
authors.lastname: Osterode
authors.forename: Margarete
authors.initials: M
authors.lastname: Goppelt-Struebe
authors.forename: Dorette
authors.initials: D
authors.lastname: Raaz
authors.forename: Atilla
authors.initials: A
authors.lastname: Yilmaz
authors.forename: Werner G
authors.initials: WG
authors.lastname: Daniel
authors.forename: Christoph D
authors.initials: CD
authors.lastname: Garlichs
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D050197:Atherosclerosis / Q000276:immunology*; D002448:Cell Adhesion / Q000187:drug effects; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003198:Computer Simulation; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D008955:Models, Cardiovascular; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D009716:Numerical Analysis, Computer-Assisted; D000077185:Resveratrol; D019821:Simvastatin / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology; D013314:Stress, Mechanical; D013312:Stress, Physiological; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D019040:E-Selectin; D016328:NF-kappa B; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D019821:Simvastatin; D000077185:Resveratrol