Shear-induced endothelial mechanotransduction: the interplay between reactive oxygen species (ROS) and nitric oxide (NO) and the pathophysiological implications

Abstract

Hemodynamic shear stress, the blood flow-generated frictional force acting on the vascular endothelial cells, is essential for endothelial homeostasis under normal physiological conditions. Mechanosensors on endothelial cells detect shear stress and transduce it into biochemical signals to trigger vascular adaptive responses. Among the various shear-induced signaling molecules, reactive oxygen species (ROS) and nitric oxide (NO) have been implicated in vascular homeostasis and diseases. In this review, we explore the molecular, cellular, and vascular processes arising from shear-induced signaling (mechanotransduction) with emphasis on the roles of ROS and NO, and also discuss the mechanisms that may lead to excessive vascular remodeling and thus drive pathobiologic processes responsible for atherosclerosis. Current evidence suggests that NADPH oxidase is one of main cellular sources of ROS generation in endothelial cells under flow condition. Flow patterns and magnitude of shear determine the amount of ROS produced by endothelial cells, usually an irregular flow pattern (disturbed or oscillatory) producing higher levels of ROS than a regular flow pattern (steady or pulsatile). ROS production is closely linked to NO generation and elevated levels of ROS lead to low NO bioavailability, as is often observed in endothelial cells exposed to irregular flow. The low NO bioavailability is partly caused by the reaction of ROS with NO to form peroxynitrite, a key molecule which may initiate many pro-atherogenic events. This differential production of ROS and RNS (reactive nitrogen species) under various flow patterns and conditions modulates endothelial gene expression and thus results in differential vascular responses. Moreover, ROS/RNS are able to promote specific post-translational modifications in regulatory proteins (including S-glutathionylation, S-nitrosylation and tyrosine nitration), which constitute chemical signals that are relevant in cardiovascular pathophysiology. Overall, the dynamic interplay between local hemodynamic milieu and the resulting oxidative and S-nitrosative modification of regulatory proteins is important for ensuing vascular homeostasis. Based on available evidence, it is proposed that a regular flow pattern produces lower levels of ROS and higher NO bioavailability, creating an anti-atherogenic environment. On the other hand, an irregular flow pattern results in higher levels of ROS and yet lower NO bioavailability, thus triggering pro-atherogenic effects.

Comparing the spectral components of laser Doppler flowmetry and photoplethysmography signals for the assessment of the vascular response to hyperoxia

“…The NO d activity decreased in both signals. Although this decrease was not statistically significant, it is supported by previous results which suggests that hyperoxia inhibits NO synthase and creates reactive oxygen species (ROS) which react with and destroys NO, thereby decreasing the NO-mediated vasodilation (18) . As for the NO i activity, it showed a decrease in LDF but an increase in PPG.…”

“…minuiu em ambos os sinais. Embora esta diminuição não tenha sido estatisticamente significativa, ela é apoiada por resultados anteriores que sugerem que a hiperóxia inibe a NO sintase e cria espécies de oxigénio reactivas (ERO) que reagem com o NO, destruindo-o, diminuindo assim a vasodilatação mediada pelo próprio NO (18) . Quanto à atividade NO i , ela mostrou uma diminuição na FLD, mas um aumento na FPG.…”

Nrf2 as an Endothelial Mechanosensitive Transcription Factor

“…42 An increase in the generation of ROS during OS can directly decrease the bioavailability of NO and form reactive nitrogen species such as peroxynitrite, 43 which can further increase ROS production and oxidative stress by oxidizing BH 4 resulting in uncoupling of eNOS to synthesize more superoxide. 23 The onset of both OS and US in cultured human umbilical vein EC (HUVEC) has been demonstrated to enhance NADPH oxidase activity.…”

“…11 The onset of either OS or US can result in the generation of ROS by EC, which is likely to be a major mechanism for the activation of Nrf2 signaling in response to shear as treatment with the antioxidant N-acetylcysteine attenuates this. 11,42,58 It is also possible that NO can both activate protein kinase C and modify cysteine residues on Keap-1 acting as an additional mechanism to augment Nrf2 activity.…”

Neuropeptide Y reduces migration capacity of human choriocarcinomacell line by altering oxidative/antioxidative status

“…By stimulating the generation of these reactive oxygen molecules, which can alter levels of free NO (Jaimes et al, 2001;Hsieh et al, 2014), NPY could be an important factor in depletion of cell migration dependent on NOmediated pathways. In this study we investigated the modulatory capacity of NPY on the mobility of a human choriocarcinoma cytotrophoblastic cell line by examining its effects on the oxidative/antioxidative balance and bioavailability of NO.…”