eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases

Lorenzo, Annarita Di; Lin, Michelle I.; Murata, Takahisa; Landskroner-Eiger, Shira; Schleicher, Michael; Kothiya, Milankumar; Iwakiri, Yasuko; Wang, Yuanyuan; Huang, Paul L.; Sessa, William C.

doi:10.1242/jcs.153601

Cited by 26 publications

(29 citation statements)

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“…NO-induced phosphorylation of VE-cadherin disrupts endothelial barrier in human dermal microvascular endothelial cells [17], and NO-induced S-nitrosylation of b-catenin has a similar effect in bovine aortic endothelial cells [18]. In this study, we showed that VEGF increases eNOS phosphorylation at residue Ser1177 in mouse ears, indicating NO production.…”

Section: Discussionsupporting

confidence: 56%

“…Although most studies have attempted to reveal the mechanism by which VEGF regulates endothelial barrier formation [15,17,20], comprehensive studies focusing on the effect of VEGF on both, blood flow change and endothelial barrier formation, are still needed. In this study, we showed that VEGF-induced hyper-permeability is accompanied by an increase in blood flow and a disruption of endothelial barrier formation in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Chen et al reported that VEGF phosphorylates VE-cadherin, and b-catenin [15], whereas Gavard et al showed that VEGF induces endocytosis of VE-cadherin [16]. Moreover, other investigators showed that VEGF activates eNOS, leading to NO production and cytoskeleton rearrangements [17], and nitrosylates b-catenin [18]. In addition, NO appeared to plays an important role in VEGF-induced vascular hyper-permeability.…”

Section: Introductionmentioning

confidence: 99%

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VEGF-induced blood flow increase causes vascular hyper-permeability in vivo

Ashina

Tsubosaka

Kobayashi

et al. 2015

Biochemical and Biophysical Research Communications

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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VEGF-induced blood flow increase causes vascular hyper-permeability in vivo

Ashina

Tsubosaka

Kobayashi

et al. 2015

Biochemical and Biophysical Research Communications

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“…Similarly, transgenic mice made to overexpress eNOS were protected in a model of endotoxemia, with an associated reduction in pulmonary capillary leak, suggesting a protective role of eNOS abundance (16). Despite a potential protective role for eNOS in endothelial permeability, there are other studies demonstrating that, for VEGF-mediated permeability, the loss of eNOS, protected against permeability (34). Given these discrepant data, it is likely that eNOS regulation of permeability and cytokine production is ligand and stimulus specific.…”

Section: Discussionmentioning

confidence: 99%

Endothelial nitric oxide synthase modulates Toll‐like receptor 4–mediated IL‐6 production and permeabilityvianitric oxide‐independent signaling

et al. 2018

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Endothelial dysfunction, characterized by changes in eNOS, is a common finding in chronic inflammatory vascular diseases. These states are associated with increased infectious complications. We hypothesized that alterations in eNOS would enhance the response to LPS-mediated TLR4 inflammation. Human microvascular endothelial cells were treated with sepiapterin or N-nitro-L-arginine methylester (L-NAME) to alter endogenous NO production, and small interfering RNA to knockdown eNOS. Alterations of endogenous NO by sepiapterin, and L-NAME provided no significant changes to LPS inflammation. In contrast, eNOS knockdown greatly enhanced endothelial IL-6 production and permeability in response to LPS. Knockdown of eNOS enhanced LPS-induced p38. Inhibition of p38 with SB203580 prevented IL-6 production, without altering permeability. Knockdown of p38 impaired NF-κB activation. Physical interaction between p38 and eNOS was demonstrated by immunoprecipitation, suggesting a novel, NO-independent mechanism for eNOS regulation of TLR4. In correlation, biopsy samples in patients with systemic lupus erythematous showed reduced eNOS expression with associated elevations in TLR4 and p38, suggesting an in vivo link. Thus, reduced expression of eNOS, as seen in chronic inflammatory disease, was associated with enhanced TLR4 signaling through p38. This may enhance the response to infection in patients with chronic inflammatory conditions.-Stark, R. J., Koch, S. R., Choi, H., Mace, E. H., Dikalov, S. I., Sherwood, E. R., Lamb, F. S. Endothelial nitric oxide synthase modulates Toll-like receptor 4-mediated IL-6 production and permeability via nitric oxide-independent signaling.

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“…In addition to the above roles of SHP-2 in regulating neutrophil adhesion, recruitment, and TEM, our studies also support the hypothesis that SHP-2 regulates endothelial permeability in vivo. A variety of inflammatory mediators may damage endothelial barrier function by VE-cadherin cleavage, endocytosis, phosphorylation, or internalization (17,35,(50)(51)(52). When endothelial cells are subjected to these inflammatory mediators, Src family tyrosine kinases are activated, followed by increased phosphorylation of VE-cadherin and b-catenin and disassembly of AJs (4,12).…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell SHP‐2 negatively regulates neutrophil adhesion and promotes transmigration by enhancing ICAM‐1–VE‐cadherin interaction

et al. 2017

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Intercellular adhesion molecule-1 (ICAM-1) mediates the firm adhesion of leukocytes to endothelial cells and initiates subsequent signaling that promotes their transendothelial migration (TEM). Vascular endothelial (VE)-cadherin plays a critical role in endothelial cell-cell adhesion, thereby controlling endothelial permeability and leukocyte transmigration. This study aimed to determine the molecular signaling events that originate from the ICAM-1-mediated firm adhesion of neutrophils that regulate VE-cadherin's role as a negative regulator of leukocyte transmigration. We observed that ICAM-1 interacts with Src homology domain 2-containing phosphatase-2 (SHP-2), and SHP-2 down-regulation silencing of small interfering RNA in endothelial cells enhanced neutrophil adhesion to endothelial cells but inhibited neutrophil transmigration. We also found that VE-cadherin associated with the ICAM-1-SHP-2 complex. Moreover, whereas the activation of ICAM-1 leads to VE-cadherin dissociation from ICAM-1 and VE-cadherin association with actin, SHP-2 down-regulation prevented ICAM-1-VE-cadherin association and promoted VE-cadherin-actin association. Furthermore, SHP-2 down-regulation promoted LPS-induced neutrophil recruitment in mouse lung but delayed neutrophil extravasation. These results suggest that SHP-2- association with ICAM-1-mediates ICAM-1-induced Src activation and modulates VE-cadherin switching association with ICAM-1 or actin, thereby negatively regulating neutrophil adhesion to endothelial cells and enhancing their TEM.-Yan, M., Zhang, X., Chen, A., Gu, W., Liu, J., Ren, X., Zhang, J., Wu, X., Place, A. T., Minshall, R. D., Liu, G. Endothelial cell SHP-2 negatively regulates neutrophil adhesion and promotes transmigration by enhancing ICAM-1-VE-cadherin interaction.

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eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases

Cited by 26 publications

References 0 publications

VEGF-induced blood flow increase causes vascular hyper-permeability in vivo

VEGF-induced blood flow increase causes vascular hyper-permeability in vivo

Endothelial nitric oxide synthase modulates Toll‐like receptor 4–mediated IL‐6 production and permeabilityvianitric oxide‐independent signaling

Endothelial cell SHP‐2 negatively regulates neutrophil adhesion and promotes transmigration by enhancing ICAM‐1–VE‐cadherin interaction

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