scholarly journals Regulation of endothelial barrier function by p120-catenin∙VE-cadherin interaction

2017 ◽  
Vol 28 (1) ◽  
pp. 85-97 ◽  
Author(s):  
Joshua P. Garrett ◽  
Anthony M. Lowery ◽  
Alejandro P. Adam ◽  
Andrew P. Kowalczyk ◽  
Peter A. Vincent
Keyword(s):  
Barrier Function ◽  
Electrical Resistance ◽  
Vascular Endothelial ◽  
Transendothelial Electrical Resistance ◽  
Endothelial Barrier Function ◽  
P120 Catenin ◽  
Vascular Endothelial Cadherin ◽  
Phosphorylated Form ◽  
Defective Mutant ◽  
Sprout Formation

Endothelial p120-catenin (p120) maintains the level of vascular endothelial cadherin (VE-Cad) by inhibiting VE-Cad endocytosis. Loss of p120 results in a decrease in VE-Cad levels, leading to the formation of monolayers with decreased barrier function (as assessed by transendothelial electrical resistance [TEER]), whereas overexpression of p120 increases VE-Cad levels and promotes a more restrictive monolayer. To test whether reduced endocytosis mediated by p120 is required for VE-Cad formation of a restrictive barrier, we restored VE-Cad levels using an endocytic-defective VE-Cad mutant. This endocytic-defective mutant was unable to rescue the loss of TEER associated with p120 or VE-Cad depletion. In contrast, the endocytic-defective mutant was able to prevent sprout formation in a fibrin bead assay, suggesting that p120•VE-Cad interaction regulates barrier function and angiogenic sprouting through different mechanisms. Further investigation found that depletion of p120 increases Src activity and that loss of p120 binding results in increased VE-Cad phosphorylation. In addition, expression of a Y658F–VE-Cad mutant or an endocytic-defective Y658F–VE-Cad double mutant were both able to rescue TEER independently of p120 binding. Our results show that in addition to regulating endocytosis, p120 also allows the phosphorylated form of VE-Cad to participate in the formation of a restrictive monolayer.

Augmentation of Vascular Endothelial Barrier Function by Heparin and Low Molecular Weight Heparin

1995 ◽  
Vol 73 (04) ◽  
pp. 706-712 ◽  
Author(s):  
P G Bannon ◽  
Mi-Jurng Kim ◽  
R T Dean ◽  
J Dawes
Keyword(s):  
Barrier Function ◽  
Umbilical Vein ◽  
Interleukin 1 ◽  
Endothelial Permeability ◽  
Endothelial Barrier ◽  
Vascular Endothelial ◽  
Transendothelial Electrical Resistance ◽  
Endothelial Barrier Function ◽  
Early Passage ◽  
Umbilical Vein Endothelial Cells

SummaryGlycosaminoglycans (GAGs) are an important component of endothelial barrier function. Early passage human umbilical vein endothelial cells were grown to confluence on transparent micropore filters and barrier function assessed as transendothelial electrical resistance (TEER) and permeability to albumin and sucrose. Unfractionated heparin and the LMW heparin Clexane decreased endothelial permeability to both sucrose and albumin and increased TEER. Chondroitin 6-sulphate also augmented barrier function, but other GAGs had no effect. Interleukin-1 increased permeability to albumin and sucrose and decreased TEER. Although heparin attenuated the effect of IL-1 on TEER and sucrose permeability, it could not restore the barrier to albumin transfer. Denuded endothelial matrix presented a negligible barrier, which was not enhanced by heparin. When sulphation of endogenous GAGs was inhibited by chlorate, barrier function was compromised and was not restored by exogenous heparin. Thus heparin enhances the barrier function of resting endothelium, but cannot completely overcome the increased permeability resulting from exposure to IL-1 or substitute for endogenous GAGs.

scholarly journals Neddylated Cullin 3 is required for vascular endothelial-cadherin-mediated endothelial barrier function

2017 ◽  
Vol 108 (2) ◽  
pp. 208-215 ◽  
Author(s):  
Tomohisa Sakaue ◽  
Ayako Fujisaki ◽  
Hironao Nakayama ◽  
Masashi Maekawa ◽  
Hiromi Hiyoshi ◽  
...  
Keyword(s):  
Barrier Function ◽  
Endothelial Barrier ◽  
Vascular Endothelial ◽  
Endothelial Barrier Function ◽  
Vascular Endothelial Cadherin ◽  
Cullin 3

scholarly journals Rab11a Mediates Vascular Endothelial-Cadherin Recycling and Controls Endothelial Barrier Function

2016 ◽  
Vol 36 (2) ◽  
pp. 339-349 ◽  
Author(s):  
Zhibo Yan ◽  
Zhen-Guo Wang ◽  
Nava Segev ◽  
Sanyuan Hu ◽  
Richard D. Minshall ◽  
...  
Keyword(s):  
Barrier Function ◽  
Endothelial Barrier ◽  
Vascular Endothelial ◽  
Endothelial Barrier Function ◽  
Vascular Endothelial Cadherin

Abstract 296: The RNA-Binding Protein Quaking Maintains Endothelial Barrier Function Through Targeting Vascular Endothelial Cadherin mRNA

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Janine M van Gils ◽  
Ruben G de Bruin ◽  
Iris Schmidt ◽  
Eric P van der Veer ◽  
Marko K Roeten ◽  
...  
Keyword(s):  
High Resistance ◽  
Barrier Function ◽  
Rna Binding ◽  
Adherens Junctions ◽  
Rna Binding Protein ◽  
Endothelial Barrier ◽  
Vascular Endothelial ◽  
Endothelial Monolayer ◽  
Endothelial Barrier Function ◽  
Vascular Endothelial Cadherin

Endothelial cells (ECs) form a vital barrier between the blood and the artery wall, and play a major role in the onset of atherosclerosis. Endothelial monolayer integrity is determined largely by EC-cell interactions, where vascular endothelial cadherin (VE-cadherin) is the central adhesive component at these endothelial adherens junctions. While many of the receptors and signaling proteins involved in regulating these adherens junctions have been identified, surprisingly little is known regarding their regulation at the post[[Unable to Display Character: ‐]]transcriptional level. The RNA-binding protein Qauking (QKI), originally known for its function in the nervous system, has been demonstrated to be essential for blood vessel formation. We find that QKI is highly expressed in quiescent ECs, in vitro and in vivo. In contrast, human umbilical vein ECs displayed reduced levels of QKI in response to the inflammatory stimuli TNF-α as well as in cells lacking cell-cell contacts, suggesting that QKI may act to enhance barrier function. To test this, we specifically abrogated QKI expression in ECs and measured their capacity to form a high-resistance monolayer with Electrical Cell-substrate Impedance Sensing. Silencing of QKI did not affect EC adhesion or spreading, but markedly affected the capacity to form a high resistance endothelial monolayer. Consistent with these data, and the fact that VE-cadherin mRNA contains a putative QKI-response element, the targeted reduction in QKI was accompanied by a significant reduction in VE-cadherin expression at cell junctions. Importantly, we identified a direct role for QKI in regulating VE-cadherin mRNA biology, as RNA immunoprecipitation and luciferase-reporter assays revealed that QKI can directly bind to the VE-cadherin mRNA and regulate transcript stability, respectively. In conclusion, we show that the modulation of QKI expression levels affects endothelial monolayer integrity by functioning as a critical regulator of the VE-cadherin mRNA. These studies provide novel insight into a role for post-transcriptional regulation in the maintenance of endothelial barrier function, and may have wide ranging implications for the preservation of vascular integrity in disease.

scholarly journals Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function

2014 ◽  
Vol 204 (2) ◽  
pp. 247-263 ◽  
Author(s):  
Christine Jean ◽  
Xiao Lei Chen ◽  
Ju-Ock Nam ◽  
Isabelle Tancioni ◽  
Sean Uryu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Stromal Cells ◽  
Barrier Function ◽  
Tumor Metastasis ◽  
Vascular Endothelial ◽  
Vascular Endothelial Cadherin ◽  
Tumor Growth And Metastasis ◽  
Endothelial Growth Factor

Pharmacological focal adhesion kinase (FAK) inhibition prevents tumor growth and metastasis, via actions on both tumor and stromal cells. In this paper, we show that vascular endothelial cadherin (VEC) tyrosine (Y) 658 is a target of FAK in tumor-associated endothelial cells (ECs). Conditional kinase-dead FAK knockin within ECs inhibited recombinant vascular endothelial growth factor (VEGF-A) and tumor-induced VEC-Y658 phosphorylation in vivo. Adherence of VEGF-expressing tumor cells to ECs triggered FAK-dependent VEC-Y658 phosphorylation. Both FAK inhibition and VEC-Y658F mutation within ECs prevented VEGF-initiated paracellular permeability and tumor cell transmigration across EC barriers. In mice, EC FAK inhibition prevented VEGF-dependent tumor cell extravasation and melanoma dermal to lung metastasis without affecting primary tumor growth. As pharmacological c-Src or FAK inhibition prevents VEGF-stimulated c-Src and FAK translocation to EC adherens junctions, but FAK inhibition does not alter c-Src activation, our experiments identify EC FAK as a key intermediate between c-Src and the regulation of EC barrier function controlling tumor metastasis.

scholarly journals NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy

2019 ◽  
Vol 116 (10) ◽  
pp. 4538-4547 ◽  
Author(s):  
Khalil Miloudi ◽  
Malika Oubaha ◽  
Catherine Ménard ◽  
Agnieszka Dejda ◽  
Vera Guber ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Barrier Function ◽  
Notch Pathway ◽  
Major Complication ◽  
Quiescent State ◽  
Vascular Endothelial ◽  
Notch1 Signaling ◽  
Vascular Endothelial Cadherin ◽  
Fundamental Process ◽  
Human And Mouse

Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from β-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.

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