eNOS derived nitric oxide regulates endothelial barrier function via VE cadherin and Rho GTPases

Lorenzo, Annarita Di; Lin, Michelle I.; Murata, Takahisa; Landskroner-Eiger, Shira; Schleicher, Michael; Kothiya, Milankumar; Iwakiri, Yasuko; Yu, Jun; Huang, Paul L.; Sessa, William C.

doi:10.1242/jcs.115972

Cited by 120 publications

(96 citation statements)

References 62 publications

(74 reference statements)

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“…Other GEFs, such as Tiam1, Syx and TEM4, have been shown to localize at endothelial cell-cell junctions or to co-immunoprecipitate with one of the VEcadherin complex members, but no in vitro interaction studies using peptides or GST-tagged proteins have been performed so far (Di Lorenzo et al, 2013;Lampugnani et al, 2002;Ngok et al, 2012Ngok et al, , 2013. We found that Trio had a particular affinity for the pool of VE-cadherin at (re-)assembling junctions, enabling temporally coordinated Rac1 activation.…”

Section: Discussionmentioning

confidence: 72%

A local VE-cadherin/Trio-based signaling complex stabilizes endothelial junctions through Rac1

Timmerman

Heemskerk

Kroon

et al. 2015

Journal of Cell Science

111

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Endothelial cell-cell junctions maintain a restrictive barrier that is tightly regulated to allow dynamic responses to permeability-inducing angiogenic factors, as well as to inflammatory agents and adherent leukocytes. The ability of these stimuli to transiently remodel adherens junctions depends on Rho-GTPase-controlled cytoskeletal rearrangements. How the activity of Rho-GTPases is spatio-temporally controlled at endothelial adherens junctions by guanine-nucleotide exchange factors (GEFs) is incompletely understood. Here, we identify a crucial role for the Rho-GEF Trio in stabilizing junctions based around vascular endothelial (VE)-cadherin (also known as CDH5). Trio interacts with VE-cadherin and locally activates Rac1 at adherens junctions during the formation of nascent contacts, as assessed using a novel FRET-based Rac1 biosensor and biochemical assays. The Rac-GEF domain of Trio is responsible for the remodeling of junctional actin from radial into cortical actin bundles, a crucial step for junction stabilization. This promotes the formation of linear adherens junctions and increases endothelial monolayer resistance. Collectively, our data show the importance of spatiotemporal regulation of the actin cytoskeleton through Trio and Rac1 at VE-cadherin-based cell-cell junctions in the maintenance of the endothelial barrier.

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Section: Discussionmentioning

confidence: 72%

A local VE-cadherin/Trio-based signaling complex stabilizes endothelial junctions through Rac1

Timmerman

Heemskerk

Kroon

et al. 2015

Journal of Cell Science

111

View full text Add to dashboard Cite

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“…The left and right ventricles were dissected, dried overnight at 55°C, and weighed. Albumin-bound Evans Blue dye was extracted from the myocardial tissue by addition of formamide, as previously described (82). Extravasated Evans Blue was measured spectrophotometrically at 620 nm using a standard curve of Evans Blue in formamide.…”

Section: Methodsmentioning

confidence: 99%

Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload

et al. 2016

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We recently discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular function by inhibiting the rate-limiting enzyme, serine palmitoyltransferase (SPT), in de novo sphingolipid biosynthesis. Here, we show that endothelium-derived sphingolipids, particularly sphingosine-1-phosphate (S1P), protect the heart from inflammation, fibrosis, and dysfunction following pressure overload and that Nogo-B regulates this paracrine process. SPT activity is upregulated in banded hearts in vivo as well as in TNF-α–activated endothelium in vitro, and loss of Nogo removes the brake on SPT, increasing local S1P production. Hence, mice lacking Nogo-B, systemically or specifically in the endothelium, are resistant to the onset of pathological cardiac hypertrophy. Furthermore, pharmacological inhibition of SPT with myriocin restores permeability, inflammation, and heart dysfunction in Nogo-A/B–deficient mice to WT levels, whereas SEW2871, an S1P1 receptor agonist, prevents myocardial permeability, inflammation, and dysfunction in WT banded mice. Our study identifies a critical role of endothelial sphingolipid biosynthesis and its regulation by Nogo-B in the development of pathological cardiac hypertrophy and proposes a potential therapeutic target for the attenuation or reversal of this clinical condition.

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“…eNOS mediates increased endothelial permeability in response to VEGF through tyrosine phosphorylation of VE-cadherin and Rho GTPasedependent actin stress fiber formation. 85 Nitric oxide has been postulated to have a protective role in severe falciparum malaria. Similar to its antiinflammatory role on leukocyte recruitment, 86 it inhibits adhesion of IRBC on HDMEC in vitro.…”

Section: Host Inflammatory Mediatorsmentioning

confidence: 99%

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Gillrie

2016

Tissue Barriers

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Plasmodial species are protozoan parasites that infect erythrocytes. As such, they are in close contact with microvascular endothelium for most of the life cycle in the mammalian host. The hostparasite interactions of this stage of the infection are responsible for the clinical manifestations of the disease that range from a mild febrile illness to severe and frequently fatal syndromes such as cerebral malaria and multi-organ failure. Plasmodium falciparum, the causative agent of the most severe form of malaria, is particularly predisposed to modulating endothelial function through either direct adhesion to endothelial receptor molecules, or by releasing potent host and parasite products that can stimulate endothelial activation and/or disrupt barrier function. In this review, we provide a critical analysis of the current clinical and laboratory evidence for endothelial dysfunction during severe P. falciparum malaria. Future investigations using state-of-the-art technologies such as mass cytometry and organs-on-chips to further delineate parasite-endothelial cell interactions are also discussed.

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eNOS derived nitric oxide regulates endothelial barrier function via VE cadherin and Rho GTPases

Cited by 120 publications

References 62 publications

A local VE-cadherin/Trio-based signaling complex stabilizes endothelial junctions through Rac1

A local VE-cadherin/Trio-based signaling complex stabilizes endothelial junctions through Rac1

Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

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