Dataset Information

The C-terminus region of ?-arrestin1 modulates VE-cadherin expression and endothelial cell permeability.

ABSTRACT:

Background

The endothelial specific cell-cell adhesion molecule, VE-cadherin, modulates barrier function and vascular homeostasis. In this context, we have previously characterized that VEGF (vascular endothelial growth factor) leads to VE-cadherin phosphorylation, ?-arrestin2 recruitment and VE-cadherin internalization in mouse endothelial cells. However, exactly how this VE-cadherin/?-arrestin complex contributes to VEGF-mediated permeability in human endothelial cells remains unclear. In this study, we investigated in-depth the VE-cadherin/?-arrestin interactions in human endothelial cells exposed to VEGF.

Findings

First, we demonstrated that VEGF induces VE-cadherin internalization in a clathrin-dependent manner in human umbilical vein endothelial cells (HUVEC). In addition to the classical components of endocytic vesicles, ?-arrestin1 was recruited and bound to phosphorylated VE-cadherin. Molecular mapping of this interaction uncovered that the C-terminus tail of ?-arrestin1, that comprises amino acids 375 to 418, was sufficient to directly interact with the phosphorylated form of VE-cadherin. Interestingly, the expression of the C-terminus tail of ?-arrestin1 induced loss of surface exposed-VE-cadherin, promoted monolayer disorganization and enhanced permeability. Finally, this effect relied on decreased VE-cadherin expression at the transcriptional level, through inhibition of its promoter activity.

Conclusions

Altogether, our results demonstrate that ?-arrestin1 might play multiple functions collectively contributing to endothelial barrier properties. Indeed, in addition to a direct implication in VE-cadherin endocytosis, ?-arrestin1 could also control VE-cadherin transcription and expression. Ultimately, understanding the molecular mechanisms involved in VE-cadherin function might provide therapeutic tools for many human diseases where the vascular barrier is compromised.

SUBMITTER: Hebda JK

PROVIDER: S-EPMC3669046 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Publications

The C-terminus region of β-arrestin1 modulates VE-cadherin expression and endothelial cell permeability.

Hebda Jagoda K JK Leclair Héloïse M HM Azzi Sandy S Roussel Célestin C Scott Mark Gh MG Bidère Nicolas N Gavard Julie J Gavard Julie J

Cell communication and signaling : CCS 20130528 1

<h4>Background</h4>The endothelial specific cell-cell adhesion molecule, VE-cadherin, modulates barrier function and vascular homeostasis. In this context, we have previously characterized that VEGF (vascular endothelial growth factor) leads to VE-cadherin phosphorylation, β-arrestin2 recruitment and VE-cadherin internalization in mouse endothelial cells. However, exactly how this VE-cadherin/β-arrestin complex contributes to VEGF-mediated permeability in human endothelial cells remains unclear. ...[more]

PMID: 23714586

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