Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5

Taddei, Andrea; Giampietro, Costanza; Conti, Annarita; Orsenigo, Fabrizio; Breviario, Ferruccio; Pirazzoli, Valentina; Potente, Michael; Daly, Christopher; Dimmeler, Stefanie; Dejana, Elisabetta

doi:10.1038/ncb1752

Cited by 563 publications

(590 citation statements)

References 50 publications

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“…VE-cadherin upregulates claudin-5 expression by suppressing the nuclear localization of the FoxO1-b-catenin complex that inhibits claudin-5 expression (Taddei et al, 2008); their SphK2-dependent, co-upregulation by HPC before stroke that we observed may help establish the BBBprotective phenotype we documented in HPC-treated mice.…”

Section: Discussionsupporting

confidence: 52%

Junctional Protein Regulation by Sphingosine Kinase 2 Contributes to Blood–Brain Barrier Protection in Hypoxic Preconditioning-Induced Cerebral Ischemic Tolerance

Wacker

Freie

Perfater

et al. 2012

J Cereb Blood Flow Metab

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Protection of the blood-brain barrier (BBB) is correlated with improved outcome in stroke. Sphingosine kinase (SphK)-directed production of sphingosine-1-phosphate, which we previously documented as being vital to preconditioning-induced stroke protection, mediates peripheral vascular integrity via junctional protein regulation. We used a hypoxic preconditioning (HPC) model in adult wild-type and SphK2-null mice to examine the isoform-specific role of SphK2 signaling for ischemic tolerance to transient middle cerebral artery occlusion and attendant BBB protection. Reductions in infarct volume and BBB permeability in HPC-treated mice were completely lost in SphK2-null mice. Hypoxic preconditioning-induced attenuation of postischemic BBB disruption in wild types, evidenced by reduced extravascular immunoglobulin G intensity, suggests direct protection of BBB integrity. Measurement of BBB junctional protein status in response to HPC revealed SphK2-dependent increases in triton-insoluble claudin-5 and VE-cadherin, which may serve to strengthen the BBB before stroke. Postischemic loss of VE-cadherin, occludin, and zona occludens-1 in SphK2-null mice with prior HPC suggests that SphK2-dependent protection of these adherens and tight junction proteins is compulsory for HPC to establish a vasculoprotective phenotype. Further elucidation of the mediators of this endogenous, HPC-activated lipid signaling pathway, and their role in protecting the ischemic BBB, may provide new therapeutic targets for cerebrovascular protection in stroke patients.

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Section: Discussionsupporting

confidence: 52%

Junctional Protein Regulation by Sphingosine Kinase 2 Contributes to Blood–Brain Barrier Protection in Hypoxic Preconditioning-Induced Cerebral Ischemic Tolerance

Wacker

Freie

Perfater

et al. 2012

J Cereb Blood Flow Metab

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“…Both p120 and b-catenin transcription factors that are released from adhesion complexes by permeability factors such as thrombin are known to translocate to the nucleus and activate target genes 9 . VE-cadherin clustering phosphorylates and suppresses FOXO1 via the PI3K-Akt pathway, leading to the upregulation of claudin-5 expression 8 . Here, we added another transcriptional regulatory mechanism that is triggered by VE-cadherin:…”

Section: Discussionmentioning

confidence: 99%

“…A recent study revealed that VE-cadherin is involved in the transcriptional regulation of genes, including claudin-5 (ref. 8). VE-cadherin-mediated cellcell interaction activates the PI-3/Akt pathway, leading to phosphorylation and inactivation of FoxO1 transcriptional repressor, which results in upregulation of claudin-5 (ref.…”

mentioning

confidence: 99%

“…VE-cadherin-mediated cellcell interaction activates the PI-3/Akt pathway, leading to phosphorylation and inactivation of FoxO1 transcriptional repressor, which results in upregulation of claudin-5 (ref. 8). Beta-catenin or p120 associated with VE-cadherin in adherens junctional complexes also translocates to the nucleus and activates the target genes in response to permeability-inducing factors 9 .…”

mentioning

confidence: 99%

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Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

et al. 2015

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Angiogenesis is regulated by the dynamic interaction between endothelial cells (ECs).Hippo-Yes-associated protein (YAP) signalling has emerged as a key pathway that controls organ size and tissue growth by mediating cell contact inhibition. However, the role of YAP in EC has not been defined yet. Here, we show expression of YAP in the developing front of mouse retinal vessels. YAP subcellular localization, phosphorylation and activity are regulated by VE-cadherin-mediated-EC contacts. This VE-cadherin-dependent YAP phosphorylation requires phosphoinositide 3-kinase-Akt activation. We further identify angiopoietin-2 (ANG-2) as a potential transcriptional target of YAP in regulating angiogenic activity of EC in vitro and in vivo. Overexpression of YAP-active form in EC enhances angiogenic sprouting, and this effect is blocked by ANG-2 depletion or soluble Tie-2 treatment. These findings implicate YAP as a critical regulator in angiogenesis and provide new insights into the mechanism coordinating junctional stability and angiogenic activation of ECs.

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“…We and others have shown that loss of VE-cadherin adhesive function is a key event in endothelial junction remodeling and loss of barrier integrity (Dejana, 2004;Gavard and Gutkind, 2006;Taddei et al, 2008). To this regard, we first investigated the architecture of cell-cell junctions in vGPCR-expressing endothelial cells by electron microscopy.…”

Section: Ve-cadherin-dependent Cell-cell Contacts Are Disorganized Inmentioning

confidence: 99%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-proteincoupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-c/Rac nexus in vGPCRmediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

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Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5

Cited by 563 publications

References 50 publications

Junctional Protein Regulation by Sphingosine Kinase 2 Contributes to Blood–Brain Barrier Protection in Hypoxic Preconditioning-Induced Cerebral Ischemic Tolerance

Junctional Protein Regulation by Sphingosine Kinase 2 Contributes to Blood–Brain Barrier Protection in Hypoxic Preconditioning-Induced Cerebral Ischemic Tolerance

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

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