Galectin-8 induces endothelial hyperpermeability through the eNOS pathway involving S-nitrosylation-mediated adherens junction disassembly

Zamorano, Patricia; Köning, Tania; Oyanadel, Claudia; Mardones, Gonzalo A.; Ehrenfeld, Pamela; Borić, Mauricio P.; González, Alfonso; Soza, Andrea; Sánchez, Fabiola A.

doi:10.1093/carcin/bgz002

Cited by 20 publications

(16 citation statements)

References 57 publications

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“…The regulation of endothelial permeability by eNOS in basal conditions with low level of NO production at the caveolae could be totally different than in stimulated conditions, where eNOS moves to the cytosol and also releases higher concentrations of NO. In fact, the effects of basal NO in permeability seems to be mediated by sGC-PKG pathway (Kurose et al, 1993), whereas the effects of NO induced by pro-inflammatory stimulus strongly point to S-nitrosylation as the regulatory signaling mechanism (Thibeault et al, 2011; Marin et al, 2012, Guequen et al, 2016; Zamorano et al, 2017, 2019).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-8 Secreted by Glioblastoma Cells Induces Microvascular Hyperpermeability Through NO Signaling Involving S-Nitrosylation of VE-Cadherin and p120 in Endothelial Cells

et al. 2019

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Glioblastoma is a highly aggressive brain tumor, characterized by the formation of dysfunctional blood vessels and a permeable endothelial barrier. S-nitrosylation, a post-translational modification, has been identified as a regulator of endothelial function. In this work we explored whether S-nitrosylation induced by glioblastoma tumors regulates the endothelial function. As proof of concept, we observed that S-nitrosylation is present in the tumoral microenvironment of glioblastoma in two different animal models. Subsequently, we measured S nitrosylation and microvascular permeability in EAhy296 endothelial cells and in cremaster muscle. In vitro , conditioned medium from the human glioblastoma cell line U87 activates endothelial nitric oxide synthase, causes VE-cadherin- S-nitrosylation and induces hyperpermeability. Blocking Interleukin-8 (IL-8) in the conditioned medium inhibited S-nitrosylation of VE-cadherin and hyperpermeability. Recombinant IL-8 increased endothelial permeability by activating eNOS, S-nitrosylation of VE-cadherin and p120, internalization of VE-cadherin and disassembly of adherens junctions. In vivo , IL-8 induced S-nitrosylation of VE-cadherin and p120 and conditioned medium from U87 cells caused hyperpermeability in the mouse cremaster muscle. We conclude that eNOS signaling induced by glioma cells-secreted IL-8 regulates endothelial barrier function in the context of glioblastoma involving S-nitrosylation of VE-cadherin and p120. Our results suggest that inhibiting S-nitrosylation may be an effective way to control and/or block damage to the endothelial barrier and prevent cancer progression.

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Section: Discussionmentioning

confidence: 99%

Interleukin-8 Secreted by Glioblastoma Cells Induces Microvascular Hyperpermeability Through NO Signaling Involving S-Nitrosylation of VE-Cadherin and p120 in Endothelial Cells

et al. 2019

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“…Moreover, tumour cells, which lack Gal-1, form smaller tumours with significantly less permeability in situ when transplanted into SCID mice. Similarly, Gal-8 also induces endothelial permeability in vitro and in vivo (Zamorano et al, 2019). It induces eNOS-mediated S-nitrosylation of p120-catenin and dissociation of adherens junction, both in venous endothelial cells and the mouse cremaster microcirculation.…”

Section: Angiogenesis and Vascular Leakagementioning

confidence: 95%

Galectins in the Pathogenesis of Common Retinal Disease

et al. 2021

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Diseases of the retina are major causes of visual impairment and blindness in developed countries and, due to an ageing population, their prevalence is continually rising. The lack of effective therapies and the limitations of those currently in use highlight the importance of continued research into the pathogenesis of these diseases. Vascular endothelial growth factor (VEGF) plays a major role in driving vascular dysfunction in retinal disease and has therefore become a key therapeutic target. Recent evidence also points to a potentially similarly important role of galectins, a family of β-galactoside-binding proteins. Indeed, they have been implicated in regulating fundamental processes, including vascular hyperpermeability, angiogenesis, neuroinflammation, and oxidative stress, all of which also play a prominent role in retinopathies. Here, we review direct evidence for pathological roles of galectins in retinal disease. In addition, we extrapolate potential roles of galectins in the retina from evidence in cancer, immune and neuro-biology. We conclude that there is value in increasing understanding of galectin function in retinal biology, in particular in the context of the retinal vasculature and microglia. With greater insight, recent clinical developments of galectin-targeting drugs could potentially also be of benefit to the clinical management of many blinding diseases.

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“…After binding to tumor cells, adhesion proteins through their cytosolic tails interact with cytoskeletal proteins inducing changes in the shape of endothelial cells leading to destabilization of the endothelial barrier that facilitates tumor cell transmigration (Müller et al, 2001;Tichet et al, 2015). We have demonstrated that treatment of endothelial cells with conditioned medium from breast cancer cells and cytokines that are elevated in breast cancer patients induces S-nitrosylation of endothelial barrier proteins (p120, VE-cadherin and β-catenin) promoting phosphorylation and perturbation of the interactions among these proteins that leads to their internalization, which destabilizes the endothelial barrier (Marín et al, 2012;Guequén et al, 2016;Zamorano et al, 2019). Thus, better knowledge and understanding of NO biology in cancer is of paramount importance because it regulates not only expression of adhesion proteins that promote metastasis, but also controls the endothelial barrier to promote transmigration of tumor cells and metastasis.…”

Section: No and Tumor Cell Adhesionmentioning

confidence: 99%

Role of NO and S-nitrosylation in the Expression of Endothelial Adhesion Proteins That Regulate Leukocyte and Tumor Cell Adhesion

et al. 2020

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Galectin-8 induces endothelial hyperpermeability through the eNOS pathway involving S-nitrosylation-mediated adherens junction disassembly

Cited by 20 publications

References 57 publications

Interleukin-8 Secreted by Glioblastoma Cells Induces Microvascular Hyperpermeability Through NO Signaling Involving S-Nitrosylation of VE-Cadherin and p120 in Endothelial Cells

Interleukin-8 Secreted by Glioblastoma Cells Induces Microvascular Hyperpermeability Through NO Signaling Involving S-Nitrosylation of VE-Cadherin and p120 in Endothelial Cells

Galectins in the Pathogenesis of Common Retinal Disease

Role of NO and S-nitrosylation in the Expression of Endothelial Adhesion Proteins That Regulate Leukocyte and Tumor Cell Adhesion

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