Regulation of Endothelial Barrier Function

Yuan, Sarah Y.; Rigor, Robert R.

doi:10.4199/c00025ed1v01y201101isp013

Cited by 114 publications

(155 citation statements)

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“…Actin filaments are linear polymers of filamentous actin formed by actin polymerization, and under normal physiological conditions they distributed randomly throughout the cell. Various hyperpermeability-inducing agents are known to induce the reorganization of actin filaments into stress fibers that are linear parallel bundles across the cell interior (34,35). Increased F-actin stress fiber formation most often is associated with endothelial barrier dysfunction and hyperpermeability (35) The stress fiber formation that occurs following IL-1␤ treatment may also involve tight junction cleavage via the Ras homolog gene family member A (RhoA)-dependent mechanisms leading to BBB permeability.…”

Section: Discussionmentioning

confidence: 99%

“…Various hyperpermeability-inducing agents are known to induce the reorganization of actin filaments into stress fibers that are linear parallel bundles across the cell interior (34,35). Increased F-actin stress fiber formation most often is associated with endothelial barrier dysfunction and hyperpermeability (35) The stress fiber formation that occurs following IL-1␤ treatment may also involve tight junction cleavage via the Ras homolog gene family member A (RhoA)-dependent mechanisms leading to BBB permeability. RhoA-mediated mechanisms also activate cell division control protein (Cdc42), which plays an important role in maintaining the tight junction integrity and actin cytoskeletal assembly (36).…”

Section: Discussionmentioning

confidence: 99%

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Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Alluri

Grimsley²,

Shaji

et al. 2016

Journal of Biological Chemistry

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Edited by Paul FraserBlood-brain barrier (BBB) breakdown and the associated microvascular hyperpermeability followed by brain edema are hallmark features of several brain pathologies, including traumatic brain injuries (TBI). Recent studies indicate that pro-inflammatory cytokine interleukin-1␤ (IL-1␤) that is upregulated following traumatic injuries also promotes BBB dysfunction and hyperpermeability, but the underlying mechanisms are not clearly known. The objective of this study was to determine the role of calpains in mediating BBB dysfunction and hyperpermeability and to test the effect of calpain inhibition on the BBB following traumatic insults to the brain. In these studies, rat brain microvascular endothelial cell monolayers exposed to calpain inhibitors (calpain inhibitor III and calpastatin) or transfected with calpain-1 siRNA demonstrated attenuation of IL-1␤-induced monolayer hyperpermeability. Calpain inhibition led to protection against IL-1␤-induced loss of zonula occludens-1 (ZO-1) at the tight junctions and alterations in F-actin cytoskeletal assembly. IL-1␤ treatment had no effect on ZO-1 gene (tjp1) or protein expression. Calpain inhibition via calpain inhibitor III and calpastatin decreased IL-1␤-induced calpain activity significantly (p < 0.05). IL-1␤ had no detectable effect on intracellular calcium mobilization or endothelial cell viability. Furthermore, calpain inhibition preserved BBB integrity/permeability in a mouse controlled cortical impact model of TBI when studied using Evans blue assay and intravital microscopy. These studies demonstrate that calpain-1 acts as a mediator of IL-1␤-induced loss of BBB integrity and permeability by altering tight junction integrity, promoting the displacement of ZO-1, and disorganization of cytoskeletal assembly. IL-1␤-mediated alterations in permeability are neither due to the changes in ZO-1 expression nor cell viability. Calpain inhibition has beneficial effects against TBI-induced BBB hyperpermeability.The blood-brain barrier (BBB) 2 plays an important role in maintaining the homeostasis of the brain. Blood-brain barrier breakdown and the associated hyperpermeability are hallmark features of several brain pathologies and injuries. The BBB is mainly composed of the cerebral endothelial cells and the tight junctions (TJs) between them (1). TJs between the neighboring endothelial cells include transmembrane TJs, i.e. occludin, claudins, junctional adhesion molecules, etc., and membranebound TJs, i.e. zonula occludens (1). Zonula occludens play an important role in regulating BBB permeability by binding to both transmembrane tight junctions and actin cytoskeleton intracellularly (2). Various mediators of inflammation are shown to modulate BBB breakdown and permeability in a variety of pathologies (3). Blood-brain barrier breakdown and the associated hyperpermeability is the leading cause of brain edema and elevated intracranial pressure followed by decreased perfusion pressure leading to poor clinical outcomes in traumatic brain injury (TBI) (4).I...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Alluri

Grimsley²,

Shaji

et al. 2016

Journal of Biological Chemistry

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“…In many examples, microvascular barrier dysfunction was mediated through increased endothelial MLCK-dependent actomyosin contractility (32,33,41). Likewise, in several studies (20,23,26,28) of BBB dysfunction during focal brain tissue injury, hypoxia, and other neuroinflammatory conditions, BBB dysfunction was shown to depend on MLCK activity.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium

Rigor

Beard

Litovka

et al. 2012

American Journal of Physiology-Cell Physiology

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Rigor RR, Beard RS Jr, Litovka OP, Yuan SY. Interleukin-1␤-induced barrier dysfunction is signaled through PKC-in human brain microvascular endothelium. Am J Physiol Cell Physiol 302: C1513-C1522, 2012. First published March 7, 2011 doi:10.1152/ajpcell.00371.2011.-Blood-brain barrier dysfunction is a serious consequence of inflammatory brain diseases, cerebral infections, and trauma. The proinflammatory cytokine interleukin (IL)-1␤ is central to neuroinflammation and contributes to brain microvascular leakage and edema formation. Although it is well known that IL-1␤ exposure directly induces hyperpermeability in brain microvascular endothelium, the molecular mechanisms mediating this response are not completely understood. In the present study, we found that exposure of the human brain microvascular endothelium to IL-1␤ triggered activation of novel PKC isoforms ␦, , and , followed by decreased transendothelial electrical resistance (TER). The IL-1␤-induced decrease in TER was prevented by small hairpin RNA silencing of PKC-or by treatment with the isoform-selective PKC inhibitor Gö6976 but not by PKC inhibitors that are selective for all PKC isoforms other than PKC-. Decreased TER coincided with increased phosphorylation of regulatory myosin light chain and with increased proapoptotic signaling indicated by decreased uptake of mitotracker red in response to IL-1␤ treatment. However, neither of these observed effects were prevented by Gö6976 treatment, indicating lack of causality with respect to decreased TER. Instead, our data indicated that the mechanism of decreased TER involves PKC--dependent phosphorylation of the tight junction protein zona occludens (ZO)-1. Because IL-1␤ is a central inflammatory mediator, our interpretation is that inhibition of PKC-or inhibition of ZO-1 phosphorylation could be viable strategies for preventing blood-brain barrier dysfunction under a variety of neuroinflammatory conditions.

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“…Importantly, nmMlck-isoform-specific knockout (nmmlck 2/2 ) mice demonstrate a phenotype devoid of cardiovascular defects, yet these mice display an attenuated vascular inflammatory response to acute lung injury (Wainwright et al, 2003), severe burns (Reynoso et al, 2007), atherosclerosis (Sun et al, 2011) and improved survival in endotoxic shock (Ranaivo et al, 2007). Although the role of nmMlck in mediating both the opening of endothelial cell-cell junctions and the paracellular hyperpermeability response to proinflammatory agents (including histamine, thrombin, ROS and activated neutrophils) has been well documented (reviewed in Yuan and Rigor, 2010), the role of nmMlck in IL-1b-mediated dysfunction of the BBB has not been investigated. Because nmMlck has been shown to be involved in dissociating b-catenin from VEcadherin at the adherens junction (Sun et al, 2011), in this study, we hypothesized that nmMlck modulates IL-1b-mediated downregulation of Cldn5 and dysfunction of the BMVEC barrier in a manner that involves b-catenin activation, nuclear translocation and repression of the Cldn5 gene (Fig.…”

Section: Introductionmentioning

confidence: 99%

Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells

Beard

Haines

et al. 2014

Journal of Cell Science

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Aberrant elevation in the levels of the pro-inflammatory cytokine interleukin-1b (IL-1b) contributes to neuroinflammatory diseases. Blood-brain barrier (BBB) dysfunction is a hallmark phenotype of neuroinflammation. It is known that IL-1b directly induces BBB hyperpermeability but the mechanisms remain unclear. Claudin-5 (Cldn5) is a tight junction protein found at endothelial cell-cell contacts that are crucial for maintaining brain microvascular endothelial cell (BMVEC) integrity. Transcriptional regulation of Cldn5 has been attributed to the transcription factors b-catenin and forkhead box protein O1 (FoxO1), and the signaling molecules regulating their nuclear translocation. Non-muscle myosin light chain kinase (nmMlck, encoded by the Mylk gene) is a key regulator involved in endothelial hyperpermeability, and IL-1b has been shown to mediate nmMlck-dependent barrier dysfunction in epithelia. Considering these factors, we tested the hypothesis that nmMlck modulates IL-1b-mediated downregulation of Cldn5 in BMVECs in a manner that depends on transcriptional repression mediated by b-catenin and FoxO1. We found that treating BMVECs with IL-1b induced barrier dysfunction concomitantly with the nuclear translocation of b-catenin and FoxO1 and the repression of Cldn5. Most importantly, using primary BMVECs isolated from mice null for nmMlck, we identified that Cldn5 repression caused by b-catenin and FoxO1 in IL-1b-mediated barrier dysfunction was dependent on nmMlck.

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Regulation of Endothelial Barrier Function

Cited by 114 publications

References 433 publications

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium

Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells

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