Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo

Orsenigo, Fabrizio; Giampietro, Costanza; Ferrari, Alberto; Corada, Monica; Galaup, Ariane; Sigismund, Sara; Ristagno, Giuseppe; Maddaluno, Luigi; Koh, Gou Young; Franco, Davide; Kurtcuoglu, Vartan; Poulikakos, Dimos; Bałuk, Peter; McDonald, Donald M.; Lampugnani, Maria Grazia; Dejana, Elisabetta

doi:10.1038/ncomms2199

Cited by 409 publications

(523 citation statements)

References 61 publications

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“…Studies by Vestweber have shown that phosphorylation of the VE-cadherin tyrosine residues Y658 and Y685 regulated endothelial permeability, whereas phosphorylation of Y731 mediated leukocyte extravasation across AJs (21,26,33). Since we identified that these 3 residues were dephosphorylated by HIF2α-induced VE-PTP expression, we addressed the possibility that HIF2α is protective in models of sepsis on the basis of the dephosphorylation switch mechanism described above.…”

Section: Discussionmentioning

confidence: 99%

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

Gong¹,

Rehman²,

Tang³

et al. 2015

J. Clin. Invest.

119

132

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Section: Discussionmentioning

confidence: 99%

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

Gong¹,

Rehman²,

Tang³

et al. 2015

J. Clin. Invest.

119

132

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“…Whichever the case is, mechanical perturbation at the VE-cadherin molecular scale may actually induce the cascade that leads to leakiness. This notion is supported by a study showing that macroscopic hydrodynamic stress on endothelial cells could bring about phosphorylation of VE-cadherin 32 .…”

Section: Discussionmentioning

confidence: 78%

Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE–cadherin

et al. 2013

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The use of nanomaterials has raised safety concerns, as their small size facilitates accumulation in and interaction with biological tissues. Here we show that exposure of endothelial cells to TiO 2 nanomaterials causes endothelial cell leakiness. This effect is caused by the physical interaction between TiO 2 nanomaterials and endothelial cells' adherens junction protein VE-cadherin. As a result, VE-cadherin is phosphorylated at intracellular residues (Y658 and Y731), and the interaction between VE-cadherin and p120 as well as b-catenin is lost. The resulting signalling cascade promotes actin remodelling, as well as internalization and degradation of VE-cadherin. We show that injections of TiO 2 nanomaterials cause leakiness of subcutaneous blood vessels in mice and, in a melanoma-lung metastasis mouse model, increase the number of pulmonary metastases. Our findings uncover a novel non-receptor-mediated mechanism by which nanomaterials trigger intracellular signalling cascades via specific interaction with VE-cadherin, resulting in nanomaterial-induced endothelial cell leakiness.

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“…Instead, IL-6 caused JAKdependent phosphorylation of Stat and VE-cadherin, VE-cadherin internalization, disassembly of AJs, and increased EC permeability. VE-cadherin internalization is triggered by serine/threonine or tyrosine phosphorylation mediated by p21 activated kinase (40) or Src kinase family (41,42). The JAK-dependent mechanism of IL-6-induced endothelial permeability involved downstream activation of Src, as Jak inhibitor abolished Src phosphorylation at Y-416, reflecting its activation, whereas both Jak and Src inhibitors suppressed phosphorylation of VE-cadherin ( Figure 6F) and VE-cadherin disappearance from cell junctions (data not shown).…”

Section: Discussionmentioning

confidence: 91%

Selective Role of Vinculin in Contractile Mechanisms of Endothelial Permeability

Birukova

Shah

Tian

et al. 2016

Am J Respir Cell Mol Biol

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Increased vascular endothelial cell (EC) permeability is a result of intercellular gap formation that may be induced by contractiondependent and contraction-independent mechanisms. This study investigated a role of the adaptor protein vinculin in EC permeability induced by contractile (thrombin) and noncontractile (IL-6) agonists. Although thrombin and IL-6 caused a similar permeability increase in human pulmonary ECs and disrupted the association between vinculin and vascular endothelial-cadherin, they induced different patterns of focal adhesion (FA) arrangement. Thrombin, but not IL-6, caused formation of large, vinculin-positive FAs, phosphorylation of FA proteins, FA kinase and Crk-associated substrate, and increased vinculin-talin association. Thrombininduced formation of talin-positive FA and intercellular gaps were suppressed in ECs with small interfering RNA-induced vinculin knockdown. Vinculin knockdown and inhibitors of Rho kinase and myosin-II motor activity also attenuated thrombininduced EC permeability. Importantly, ectopic expression of the vinculin mutant lacking the F-actin-binding domain decreased thrombin-induced Rho pathway activation and EC permeability. In contrast, IL-6-induced EC permeability did not involve RhoA-or myosin-dependent mechanisms but engaged Janus kinase/signal transducer and activator of transcription-mediated phosphorylation and internalization of vascular endothelial-cadherin. This process was vinculin independent but Janus kinase/tyrosine kinase Src-dependent. These data suggest that vinculin participates in a contractiledependent mechanism of permeability by integrating FA with stress fibers, leading to maximal RhoA activation and EC permeability response. Vinculin inhibition does not affect contractileindependent mechanisms of EC barrier failure. This study provides, for the first time, a comparative analysis of two alternative mechanisms of vascular endothelial barrier dysfunction and defines a specific role for vinculin in the contractile type of permeability response.Keywords: cyclic stretch; Rho; focal adhesions; vascular permeability; endothelium Clinical RelevanceThis study investigates the involvement of vinculin in mechanisms of agonist-induced endothelial permeability activated by contractile and noncontractile agonists and defines the role for vinculin-driven focal adhesion-actin cytoskeleton anchoring in the propagation of Rho-dependent endothelial permeability caused by contractile agonists.The lung endothelial cells (ECs) form a semiselective barrier between circulating blood and interstitial fluid. The contractile model of EC barrier regulation (1,2) suggests that paracellular gap formation is controlled by the balance of competing contractile forces imposed by the actomyosin cytoskeleton anchored to focal adhesions (FAs), which generate centripetal tension, and adhesive cell-cell and cell-matrix tethering forces imposed by peripheral FAs and adherens junctions

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Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo

Cited by 409 publications

References 61 publications

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE–cadherin

Selective Role of Vinculin in Contractile Mechanisms of Endothelial Permeability

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