Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability

Komarova, Yulia; Kruse, Kevin; Mehta, Dolly; Malik, Asrar B.

doi:10.1161/circresaha.116.306534

Cited by 391 publications

(381 citation statements)

References 414 publications

(528 reference statements)

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“…Immune cell trafficking across blood vessels is controlled by both cell junctions and vesicles that regulate transport between or within endothelial cells (Komarova et al, 2017). During CNS autoimmune diseases, leukocytes migrate across several pathways to reach the CNS parenchyma.…”

Section: Introductionmentioning

confidence: 99%

Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation

et al. 2017

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SUMMARY Lymphocytes cross vascular boundaries via either disrupted tight junctions (TJs) or caveolae to induce tissue inflammation. In the central nervous system (CNS), Th17 lymphocytes cross the blood-brain barrier (BBB) prior to Th1 cells, yet this differential crossing is poorly understood. We have used intravital two-photon imaging of the spinal cord in wild-type and caveolae-deficient mice with fluorescently labeled endothelial TJs, to determine how TJ remodeling and caveolae regulate CNS entry of lymphocytes during the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis. We find that dynamic TJ remodeling occurs early in EAE but does not depend upon caveolar transport. Moreover, Th1 but not Th17 lymphocytes are significantly reduced in the inflamed CNS of mice lacking caveolae. Therefore, TJ remodeling facilitates Th17 migration across the BBB, whereas caveolae promote Th1 entry into the CNS. Moroever, therapies that target both TJ degradation and caveolar transcytosis may limit lymphocyte infiltration during inflammation.

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Section: Introductionmentioning

confidence: 99%

Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation

et al. 2017

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“…During inflammation, the adhesiveness of active leukocytes as well as the permeability of the endothelial monolayer increases. However, pathological sustenance of the inflammatory process as well as other factors can further maintain endothelial permeability increased, leading to edema, hemorrhage, and deleterious leukocyte infiltration (8).…”

Section: Introductionmentioning

confidence: 99%

Dasatinib Reversibly Disrupts Endothelial Vascular Integrity by Increasing Non-Muscle Myosin II Contractility in a ROCK-Dependent Manner

Kreutzman

Colom-Fernández

Jiménez

et al. 2017

Clinical Cancer Research

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Purpose: Dasatinib is a short-acting dual ABL/SRC family tyrosine kinase inhibitor (TKI), which is frequently used to treat chronic myeloid leukemia. Although very effective, patients taking dasatinib often display severe adverse effects, including pleural effusions and increased risk of bleeding primarily in the gastrointestinal tract. The actual causes of these side effects are currently undetermined. We hypothesize that endothelial cells (ECs) that line the inner walls of blood vessels and control the traffic to the underlying tissues might be involved.Experimental Design: The effects of TKIs on ECs were studied by various assays, such as real-time cell impedance measurements, live-cell microscopy, wound healing, Western blot, and an in vivo model.Results: Dasatinib uniquely causes a profound, dose-dependent disorganization of the EC monolayers. Dasatinib promoted the disassembly of cell-cell contacts, altered cell-matrix contacts, and further altered the wound healing. A key observation is that this effect is fully reversible after drug washout. In line with these in vitro observations, intraperitoneal administration of dasatinib to mice caused significant vascular leakage in the intestine. The underlying molecular mechanism of dasatinib-induced reorganization of the actin involves ROCK activation, which increases the amount of the phosphorylation of myosin light chain and consequently activates the non-muscle myosin II.Conclusions: Our data are consistent with a scenario in which dasatinib triggers a transient increase in vascular leakage that probably contributes to adverse effects such as bleeding diathesis and pleural effusions.

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“…To the Editor: The recent review by Komarova et al 1 on Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability addresses a central topic in vascular biology that plays an important role in diabetes mellitus, cancer, and other common disorders. However, several statements in the review overlook evidence that does not support the views they promote:…”

Section: Letter By Horowitz Regarding Article "Protein Interactions mentioning

confidence: 99%

Letter by Horowitz Regarding Article, “Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability”

Horowitz

2017

Circulation Research

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Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability

Cited by 391 publications

References 414 publications

Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation

Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation

Dasatinib Reversibly Disrupts Endothelial Vascular Integrity by Increasing Non-Muscle Myosin II Contractility in a ROCK-Dependent Manner

Letter by Horowitz Regarding Article, “Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability”

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