VE-Cadherin-Mediated Cell-Cell Interaction Suppresses Sprouting via Signaling to MLC2 Phosphorylation

Abraham, Sabu; Yeo, Margaret; Montero-Balaguer, Mercedes; Paterson, Hugh; Dejana, Elisabetta; Marshall, Christopher J.; Mavria, Georgia

doi:10.1016/j.cub.2009.02.057

Cited by 145 publications

(149 citation statements)

References 29 publications

(45 reference statements)

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“…Our data suggest that the higher strength of adhesion provided by laminin 511 acts to stabilize VE‐cadherin at cell–cell junctions by inhibiting its endocytosis, reflected in the enhanced association with p120 catenin (Xiao et al , 2005; Chiasson et al , 2009). This enhanced junctional localization of VE‐cadherin induced by laminin 511 correlated with increased cell–cell adhesion strength as shown in the dual pipette‐pulling assays and, in vivo , by the enhanced junctional phospho‐myosin II staining in Lama4 −/− mice, which show an aberrant ubiquitous laminin α5 expression (van Nieuw Amerongen et al , 2007; Abraham et al , 2009). Others have shown that the strength of endothelial cell adhesion to the extracellular matrix affects the force that can be generated at junctions, across the force‐sensing molecule PECAM‐1 (Collins et al , 2014).…”

Section: Discussionmentioning

confidence: 89%

Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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Shear detection and mechanotransduction by arterial endothelium requires junctional complexes containing PECAM‐1 and VE‐cadherin, as well as firm anchorage to the underlying basement membrane. While considerable information is available for junctional complexes in these processes, gained largely from in vitro studies, little is known about the contribution of the endothelial basement membrane. Using resistance artery explants, we show that the integral endothelial basement membrane component, laminin 511 (laminin α5), is central to shear detection and mechanotransduction and its elimination at this site results in ablation of dilation in response to increased shear stress. Loss of endothelial laminin 511 correlates with reduced cortical stiffness of arterial endothelium in vivo, smaller integrin β1‐positive/vinculin‐positive focal adhesions, and reduced junctional association of actin–myosin II. In vitro assays reveal that β1 integrin‐mediated interaction with laminin 511 results in high strengths of adhesion, which promotes p120 catenin association with VE‐cadherin, stabilizing it at cell junctions and increasing cell–cell adhesion strength. This highlights the importance of endothelial laminin 511 in shear response in the physiologically relevant context of resistance arteries.

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Section: Discussionmentioning

confidence: 89%

Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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“…Nevertheless, the permeability regulating activity of Brag2 does not explain the observed inhibition of EC migration and angiogenic sprouting induced by the knockdown of Brag2 in our study. Indeed, VE-Cadherin-induced cell-cell interactions were shown to block EC migration and angiogenic sprouting [1]. So, one would expect that, since silencing of Brag2 reduces VE-Cadherin-mediated cell-cell adhesion (adherens junctions) and increases vascular permeability ( [20] and our unpublished data), would rather lead to a promigratory and proangiogenic EC phenotype.…”

Section: Discussionmentioning

confidence: 93%

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

et al. 2014

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b1-Integrins are essential for angiogenesis. The mechanisms regulating integrin function in endothelial cells (EC) and their contribution to angiogenesis remain elusive. Brag2 is a guanine nucleotide exchange factor for the small Arf-GTPases Arf5 and Arf6. The role of Brag2 in EC and angiogenesis and the underlying molecular mechanisms remain unclear. siRNA-mediated Brag2-silencing reduced EC angiogenic sprouting and migration. Brag2-siRNA transfection differentially affected a5b1-and aVb3-integrin function: specifically, Brag2-silencing increased focal/fibrillar adhesions and adhesion on b1-integrin ligands (fibronectin and collagen), while reducing the adhesion on the aVb3-integrin ligand, vitronectin. Consistent with these results, Brag2-silencing enhanced surface expression of a5b1-integrin, while reducing surface expression of aVb3-integrin. Mechanistically, Brag2-mediated aVb3-integrin-recycling and b1-integrin endocytosis and specifically of the active/matrix-bound a5b1-integrin present in fibrillar/focal adhesions (FA), suggesting that Brag2 contributes to the disassembly of FA via b1-integrin endocytosis. Arf5 and Arf6 are promoting downstream of Brag2 angiogenic sprouting, b1-integrin endocytosis and the regulation of FA. In vivo silencing of the Brag2-orthologues in zebrafish embryos using morpholinos perturbed vascular development. Furthermore, in vivo intravitreal injection of plasmids containing Brag2-shRNA reduced pathological ischemia-induced retinal and choroidal neovascularization. These data reveal that Brag2 is essential for developmental and pathological angiogenesis by promoting EC sprouting through regulation of adhesion by mediating b1-integrin internalization and link for the first time the process of b1-integrin endocytosis with angiogenesis.

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“…VE-cadherin promotes Rho-kinase activity, MLC phosphorylation and actomyosin contractility, which, in turn, enhances VE-cadherin accumulation at cell junctions and thereby vessel stability 33,34 . The small GTPase Rap1, another important regulator of endothelial junction formation 35 , has been recently shown to promote VE-cadherin-dependent cell-cell adhesion through Cdc42, the kinase MRCK, MLC phosphorylation and actin reorganization 36 .…”

Section: Inducible Inactivation Of Itgb1 In the Postnatal Endotheliummentioning

confidence: 99%

Integrin β1 controls VE-cadherin localization and blood vessel stability

et al. 2015

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Angiogenic blood vessel growth requires several distinct but integrated cellular activities. Endothelial cell sprouting and proliferation lead to the expansion of the vasculature and give rise to a highly branched, immature plexus, which is subsequently reorganized into a mature and stable network. Although it is known that integrin-mediated cell-matrix interactions are indispensable for embryonic angiogenesis, little is known about the function of integrins in different steps of vascular morphogenesis. Here, by investigating the integrin b1-subunit with inducible and endothelial-specific gene targeting in the postnatal mouse retina, we show that b1 integrin promotes endothelial sprouting but is a negative regulator of proliferation. In maturing vessels, integrin b1 is indispensable for proper localization of VE-cadherin and thereby cell-cell junction integrity. The sum of our findings establishes that integrin b1 has critical functions in the growing and maturing vasculature, and is required for the formation of stable, non-leaky blood vessels.

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VE-Cadherin-Mediated Cell-Cell Interaction Suppresses Sprouting via Signaling to MLC2 Phosphorylation

Cited by 145 publications

References 29 publications

Endothelial basement membrane laminin 511 is essential for shear stress response

Endothelial basement membrane laminin 511 is essential for shear stress response

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

Integrin β1 controls VE-cadherin localization and blood vessel stability

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