Activation of Rac1 by shear stress in endothelial cells mediates both cytoskeletal reorganization and effects on gene expression.
Hemodynamic shear stress is a fundamental determinant of vascular remodeling and atherogenesis. Changes in focal adhesions, cytoskeletal organization and gene expression are major responses of endothelial cells to shear stress. Here, we show that activation of the small GTPase Rac is essential for gene expression and for providing spatial information for shear stress-induced cell alignment. Fluorescence resonance energy transfer (FRET) localizes activated Rac1 in the direction of flow. This directional Rac1 activation is downstream of shear-induced new integrin binding to extracellular matrix. Additionally, Rac1 mediates flow-induced stimulation of nuclear factor kappaB (NF-kappaB) and the subsequent expression of intercellular cell adhesion molecule 1 (ICAM-1), an adhesion receptor involved in the recruitment of leukocytes to atherosclerotic plaque. These studies provide a unifying model linking three of the main responses to shear stress that mediate both normal adaptation to hemodynamic forces and inflammatory dysfunction of endothelial cells in atherosclerosis.
Tzima
Eleni
E
Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Del Pozo
Miguel Angel
MA
Kiosses
William B
WB
Mohamed
Samih A
SA
Li
Song
S
Chien
Shu
S
Schwartz
Martin Alexander
MA
D000818:Animals; D002417:Cattle; D002448:Cell Adhesion; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism*; D019281:Dimerization; D004735:Energy Transfer; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D021381:Protein Transport; D013050:Spectrometry, Fluorescence; D013314:Stress, Mechanical; D013997:Time Factors; D014162:Transfection; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D008164:Luminescent Proteins; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D049452:Green Fluorescent Proteins; D008156:Luciferases; D020558:GTP Phosphohydrolases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein