Modulation of low shear stress-induced eNOS multi-site phosphorylation and nitric oxide production via protein kinase and ERK1/2 signaling

Kong, Xiangquan; Qu, Xinliang; Li, Bing; Wang, Zhimei; Chao, Yuelin; Jiang, Xiaoyu; Wu, Wen; Chen, Shao‐Liang

doi:10.3892/mmr.2016.6060

Cited by 14 publications

(9 citation statements)

References 23 publications

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“…Therefore, it is important to understand the relationship between LSS and ROS generation. Our laboratory previously showed that LSS induces ROS in a time‐dependent manner, which may involve ERK/eNOS Thr495 (Kong et al, ; Wang et al, ). De Keulenaer et al () demonstrated that laminar shear stress (5 dyn/cm 2 ) resulted in a significant time‐dependent increase in the superoxide (O 2 −) level.…”

Section: Discussionmentioning

confidence: 98%

“…The cells were cultured in RPMI‐1640 medium supplemented with 10% fetal bovine serum (GIBICO). Upon reaching 90% confluence, the cells were digested with 0.25% trypsin (GIBICO) and transferred to slides for subsequent experiments (shear stress) as described in our previous study (Kong et al, ). When the cells on slides reach 90% confluence, we exposed cells to shear stress application.…”

Section: Methodsmentioning

confidence: 99%

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Low shear stress induces endothelial reactive oxygen species via the AT1R/eNOS/NO pathway

Chao

Zhu

et al. 2017

Journal Cellular Physiology

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Reactive oxygen species (ROS) contribute to many aspects of physiological and pathological cardiovascular processes. However, the underlying mechanism of ROS induction by low shear stress (LSS) remains unclear. Accumulating evidence has shown that the angiotensin II type 1 receptor (AT1R) is involved in inflammation, apoptosis, and ROS production. Our aim was to explore the role of AT1R in LSS-mediated ROS induction. We exposed human umbilical vein endothelial cells (HUVECs) to LSS (3 dyn/cm ) for different periods of time. Western blotting and immunofluorescence showed that LSS significantly induced AT1R expression in a time-dependent manner. Using immunohistochemistry, we also noted a similar increase in AT1R expression in the inner curvature of the aortic arch compared to the descending aorta in C57BL/6 mice. Additionally, HUVECs were cultured with a fluorescent probe, either DCFH, DHE or DAF, after being subjected to LSS. Cell chemiluminescence and flow cytometry results revealed that LSS stimulated ROS levels and suppressed nitric oxide (NO) generation in a time-dependent manner, which was reversed by the AT1R antagonist Losartan. We also found that Losartan markedly increased endothelial NO synthase (eNOS) phosphorylation at Ser(633,1177) and dephosphorylation at Thr(495), which involved AKT and ERK. Moreover, the ROS level was significantly reduced by endogenous and exogenous NO donors (L-arginine, SNP) and increased by the eNOS inhibitor L-NAME. Overall, we conclude that LSS induces ROS via AT1R/eNOS/NO.

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Low shear stress induces endothelial reactive oxygen species via the AT1R/eNOS/NO pathway

Chao

Zhu

et al. 2017

Journal Cellular Physiology

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“…As one of the substrates for Akt1, phosphorylated eNOS generates nitric oxide in EC that regulates endothelial function, including angiogenesis and vessel dilation; 53,54 eNOS can also be regulated via ERK1/2 and p38, consistent with a complex network of signaling cascades. 55,56 Knockdown of eNOS in a murine AVF model prevents the normalization of shear stress after AVF creation and impairs outward remodeling. 57 In addition, increasing eNOS activity by knockdown of caveolin-1 promotes AVF maturation, 21 consistent with our data that activation of EphrinB2 by EphB4-Fc leading to subsequent activation of Akt1, p38, and ERK1/2 increases wall thickening during venous remodeling (Fig.…”

Section: Discussionmentioning

confidence: 99%

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae

Wang

Liu

et al. 2021

Journal of Surgical Research

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Background: Arteriovenous fistulae (AVF) are the preferred mode of vascular access for hemodialysis. Before use, AVF remodel by thickening and dilating to achieve a functional conduit via an adaptive process characterized by expression of molecular markers characteristic of both venous and arterial identity. Although signaling via EphB4, a determinant of venous identity, mediates AVF maturation, the role of its counterpart EphrinB2, a determinant of arterial identity, remains unclear. We hypothesize that EphrinB2 signaling is active during AVF maturation and may be a mechanism of venous remodeling. Methods: Aortocaval fistulae were created or sham laparotomy was performed in C57Bl/6 mice, and specimens were examined on Days 7 or 21. EphrinB2 reverse signaling was activated with EphB4-Fc applied periadventitially in vivo and in endothelial cell culture medium in vitro. Downstream signaling was assessed using immunoblotting and immunofluorescence. Results: Venous remodeling during AVF maturation was characterized by increased expression of EphrinB2 as well as Akt1, extracellular signal-regulated kinases 1/2 (ERK1/ 2), and p38. Activation of EphrinB2 with EphB4-Fc increased phosphorylation of Eph-rinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and was associated with increased diameter and wall thickness in the AVF. Both mouse and human endothelial cells treated with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and increased endothelial cell tube formation and migration. Conclusions: Activation of EphrinB2 signaling by EphB4-Fc was associated with adaptive venous remodeling in vivo while activating endothelial cell function in vitro.

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“…Physiological shear stress has been demonstrated to serve an atheroprotective function by stimulating eNOS multisite phosphorylation. In our previous study, we found that LSS‑induced activation of ERK1/2/eNOS‑Thr495 served a major role in inhibiting endothelial NO synthase, which may explain the proinflammatory and proatherosclerotic properties of LSS . We further discovered that LSS strongly activated hyaluronidase 2 to degrade HA in the glycocalyx.…”

Section: Discussionmentioning

confidence: 86%

“…In our previous study, we found that LSS-induced activation of ERK1/2/eNOS-Thr495 served a major role in inhibiting endothelial NO synthase, which may explain the proinflammatory and proatherosclerotic properties of LSS. 21 We further discovered that LSS strongly activated hyaluronidase 2 to degrade HA in the glycocalyx. The dephosphorylation of eNOS-Ser-633 under LSS was triggered after HA degradation by hyaluronidase, and prevented by repairing the glycocalyx with high molecular weight hyaluronan.…”

Section: Discussionmentioning

confidence: 86%

Relationship between the endothelial glycocalyx and the extent of coronary atherosclerosis

et al. 2018

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Modulation of low shear stress-induced eNOS multi-site phosphorylation and nitric oxide production via protein kinase and ERK1/2 signaling

Cited by 14 publications

References 23 publications

Low shear stress induces endothelial reactive oxygen species via the AT1R/eNOS/NO pathway

Low shear stress induces endothelial reactive oxygen species via the AT1R/eNOS/NO pathway

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae

Relationship between the endothelial glycocalyx and the extent of coronary atherosclerosis

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