The E3 ubiquitin ligase <scp>MARCH</scp>3 controls the endothelial barrier

Leclair, Héloïse M; André-Grégoire, Gwennan; Treps, Lucas; Azzi, Sandy; Bidère, Nicolas; Gavard, Julie

doi:10.1002/1873-3468.12417

Cited by 20 publications

(11 citation statements)

References 35 publications

(68 reference statements)

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“…In vitro brain endothelial cell permeability was performed as described previously [ 15 , 72 , 73 ]. Standard protocol was used for RT-PCR [ 73 ].…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

Glioblastoma stem‐like cells secrete the pro‐angiogenic VEGF‐A factor in extracellular vesicles

Treps

Perret

Edmond

et al. 2017

J of Extracellular Vesicle

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214

188

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Glioblastoma multiforme (GBM) are mortifying brain tumours that contain a subpopulation of tumour cells with stem-like properties, termed glioblastoma stem-like cells (GSCs). GSCs largely contribute to tumour initiation, propagation and resistance to current anti-cancer therapies. GSCs are situated in perivascular niches, closely associated with brain microvascular endothelial cells, thereby involved in bidirectional molecular and cellular interactions. Moreover, extracellular vesicles are suspected to carry essential information that can adapt the microenvironment to the tumour’s needs, including tumour-induced angiogenesis. In GBM, extracellular vesicles produced by differentiated tumour cells and GSCs were demonstrated to disseminate locally and at distance. Here, we report that the pro-angiogenic pro-permeability factor VEGF-A is carried in extracellular vesicles secreted from ex vivo cultured patient-derived GSCs. Of note, extracellular vesicle-derived VEGF-A contributes to the in vitro elevation of permeability and angiogenic potential in human brain endothelial cells. Indeed, VEGF-A silencing in GSCs compromised in vitro extracellular vesicle-mediated increase in permeability and angiogenesis. From a clinical standpoint, extracellular vesicles isolated from circulating blood of GBM patients present higher levels of VEGF-A, as compared to healthy donors. Overall, our results suggest that extracellular vesicle-harboured VEGF-A targets brain endothelial cells and might impact their ability to form new vessels. Thus, tumour-released EV cargo might emerge as an instrumental part of the tumour-induced angiogenesis and vascular permeability modus operandi in GBM.

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“…In vitro brain endothelial cell permeability was performed as described previously [ 15 , 72 , 73 ]. Standard protocol was used for RT-PCR [ 73 ].…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

Glioblastoma stem‐like cells secrete the pro‐angiogenic VEGF‐A factor in extracellular vesicles

Treps

Perret

Edmond

et al. 2017

J of Extracellular Vesicle

Self Cite

214

188

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“…It has been shown that PI-3K signalling improves vascular permeability through Akt-FoxO pathway and subsequent upregulation of claudin-5 [34,35]. Akt is also a negative regulator of FoxO1 which can act as a transcriptional repressor of occludin [36]. Immunocytochemical labelling revealed fragmented staining patterns for occludin and ZO-1 in the membranes of BCECs treated with bFGF and LY29402 (Fig.…”

Section: Discussionmentioning

confidence: 98%

Concentration-dependent duality of bFGF in regulation of barrier properties of human brain endothelial cells

Kriaučiūnaitė

Pociūtė

Kaušylė

et al. 2021

Preprint

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Multiple paracrine factors regulate barrier properties of human brain capillary endothelial cells (BCECs). Understanding precise mode of action of these factors remains a challenging task because of the limited availability of functionally competent BCECs and use of serum-containing medium. In the present study we employed defined protocol for producing BCECs from human inducible pluripotent stem cells. We found that autocrine secretion of basic fibroblast growth factor (bFGF) is necessary for the establishment a tight BCECs barrier, as revealed by measurements of trans-endothelial electric resistance (TEER). In contrast, exogenous bFGF in concentrations exceeding 4 ng/ml inhibited TEER and proliferation of BCECs in a concentration-dependent manner. Exogenous bFGF did not significantly affect expression and distribution of tight junction proteins claudin-5, occludin and ZO-1. Treatment with FGF receptor blocker PD173074 (15 μM) suppressed inhibitory effects of bFGF and induced nuclear translocation of protein ZO-1. Inhibition of phosphoinositide 3-Kinase (PI-3K) with LY294002 (25 μM) significantly potentiated inhibitory effect of bFGF on TEER indicating that PI-3K signalling pathway partially suppress inhibitory effects of bFGF on TEER. In conclusion we show that autocrine bFGF secretion is necessary for the proper barrier function of BCECs, whereas exogenous bFGF suppresses barrier resistance in a concentration-dependent manner. Our findings demonstrate a dual role for bFGF in the regulation of BCEC barrier function.

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“…The MARCH3 E3 ligase also negatively regulates endothelial integrity, but in an indirect manner. In human brain ECs in which MARCH3 was downregulated, histamine-induced permeability was reduced (Leclair et al, 2016). In brain ECs transfected with siRNA targeting MARCH3, both the mRNA and protein levels of claudin-5 and occludin were increased, whereas the mRNA and protein levels of VE-cadherin were only increased slightly.…”

Section: Ubiquitin Ligases and Junctional Regulationmentioning

confidence: 93%

“…Here, MARCH3 was found to act through the transcription repressor FoxO1 to reduce the mRNA expression levels of the tight junction proteins occludin and claudin-5. Thus, MARCH3-mediated reduction of mRNAs that encode tight junction proteins impairs adherens junction stability and endothelial integrity (Leclair et al, 2016). This mechanism is thus clearly different from the ubiquitylation of claudin-5 in human brain microvascular ECs by the HECT domain E3 ubiquitin protein ligase (HECTD)1 (Rui et al, 2018).…”

Section: Ubiquitin Ligases and Junctional Regulationmentioning

confidence: 99%

Ubiquitin-based modifications in endothelial cell–cell contact and inflammation

Majolée

Kovačević

Hordijk

2019

Journal of Cell Science

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Endothelial cell-cell contacts are essential for vascular integrity and physiology, protecting tissues and organs from edema and uncontrolled invasion of inflammatory cells. The vascular endothelial barrier is dynamic, but its integrity is preserved through a tight control at different levels. Inflammatory cytokines and G-protein-coupled receptor agonists, such as histamine, reduce endothelial integrity and increase vascular leakage. This is due to elevated myosin-based contractility, in conjunction with phosphorylation of proteins at cell-cell contacts. Conversely, reducing contractility stabilizes or even increases endothelial junctional integrity. Rho GTPases are key regulators of such cytoskeletal dynamics and endothelial cell-cell contacts. In addition to signaling-induced regulation, the expression of junctional proteins, such as occludin, claudins and vascular endothelial cadherin, also controls endothelial barrier function. There is increasing evidence that, in addition to protein phosphorylation, ubiquitylation (also known as ubiquitination) is an important and dynamic post-translational modification that regulates Rho GTPases, junctional proteins and, consequently, endothelial barrier function. In this Review, we discuss the emerging role of ubiquitylation and deubiquitylation events in endothelial integrity and inflammation. The picture that emerges is one of increasing complexity, which is both fascinating and promising given the clinical relevance of vascular integrity in the control of inflammation, and of tissue and organ damage.

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The E3 ubiquitin ligase MARCH3 controls the endothelial barrier

Cited by 20 publications

References 35 publications

Glioblastoma stem‐like cells secrete the pro‐angiogenic VEGF‐A factor in extracellular vesicles

Glioblastoma stem‐like cells secrete the pro‐angiogenic VEGF‐A factor in extracellular vesicles

Concentration-dependent duality of bFGF in regulation of barrier properties of human brain endothelial cells

Ubiquitin-based modifications in endothelial cell–cell contact and inflammation

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