Mechanotransduction of endothelial oxidative stress induced by cyclic strain.
Atherosclerotic lesions display a nonuniform distribution throughout the vascular tree. Mechanical forces produced by local alterations in blood flow may play an important role in the localization of atherosclerosis. One such force, cyclic strain, has been hypothesized to promote atherogenesis by inducing oxidative stress in endothelial cells, resulting in enhanced endothelial adhesiveness for monocytes. To investigate the signal transduction systems involved, human aortic endothelial cells were plated on flexible silicone strips that were either non-coated or adsorbed with poly-L-lysine, vitronectin, fibronectin, or collagen I. Cells were then subjected to uniform sinusoidal stretch (10%) for 6 h. Endothelial superoxide anion production was increased in cells exposed to cyclic strain compared to static conditions. Furthermore, endothelial oxidative response to stretch was matrix protein-dependent, whereas cells grown on fibronectin and collagen I produced significantly more superoxide. The oxidative response to cyclic strain was reduced by coincubation with RGD peptides, blocking antibodies to alpha2- and beta-integrins antibodies, as well as inhibitors of protein kinase C. To investigate the effect of oxidative stress on gene transcription, endothelial cells grown on collagen I were transfected with an NFkappaB-sensitive luciferase construct. Cells that underwent cyclic strain displayed a tenfold induction of NFkappaB activation compared to static controls. Strain-induced luciferase activity was blunted by coincubation with RGD peptides or calphostin C. Thus, exposure of endothelial cells to cyclic strain led to integrin activation of a PKC-sensitive pathway that results in increased superoxide anion production and mobilization of NFkappaB.
Wang
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Department of Medicine, Stanford University, School of Medicine, CA 94305-5406, USA.
Proffit
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Tsao
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D001011:Aorta; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013314:Stress, Mechanical; D013481:Superoxides / Q000378:metabolism
D016023:Integrins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013481:Superoxides; D011493:Protein Kinase C