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Laminar shear stress (LSS) is a protective hemodynamic regulator of endothelial function and limits the development of atherosclerosis and other vascular wall diseases related to pathophysiological generation of reactive oxygen species. LSS activates several endothelial signaling responses, including the activation of MAPKs and eNOS. Here, we explored the mechanisms of activation of these key endothelial signaling pathways. Using the cone/plate model we found that LSS (12 dyn/cm2) rapidly promotes endothelial intracellular generation of superoxide and hydrogen peroxide (H2O2). Physiological concentrations of H2O2 (flux of 0.1 nM/min and 15 μM added extracellularly) significantly activated both eNOS and p38 MAPK. Pharmacological inhibition of NADPH oxidases (NOXs) and specific knockdown of NOX4 decreased LSS-induced p38 MAPK activation. Whereas the absence of eNOS did not alter LSS-induced p38 MAPK activation, pharmacological inhibition and knockdown of p38α MAPK blocked H2O2- and LSS-induced eNOS phosphorylation and reduced •NO levels. We propose a model in which LSS promotes the formation of signaling levels of H2O2, which in turn activate p38α MAPK and then stimulate eNOS, leading to increased •NO generation and protection of endothelial function.