Neutrophil-derived Glutamate Regulates Vascular Endothelial Barrier Function

Collard, Charles D.; Park, Kellie A.; Montalto, Michael; Alapati, Sailaja; Buras, Jon A.; Stahl, Gregory L.; Colgan, Sean P.

doi:10.1074/jbc.m110557200

Cited by 151 publications

(142 citation statements)

References 54 publications

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“…Studies have shown that BBB ECs also express both NMDA and metabotropic glutamate receptors (Krizbai et al 1998;Sharp et al 2003). Circulating inflammatory mediators have also been shown to stimulate a release of glutamate, which disrupts the BBB via metabotropic receptors (Collard et al 2002). Interestingly, in vitro studies showed that NMDA receptor activation reduces BBB integrity, whereas activation of metabotropic receptors increased BBB electrical resistance suggesting a tightening of the BBB.…”

Section: Modulation Of Channels and Transportersmentioning

confidence: 99%

The Blood–Brain Barrier

Daneman

Prat

2015

Cold Spring Harb Perspect Biol

2,533

1,829

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Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.

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Section: Modulation Of Channels and Transportersmentioning

confidence: 99%

The Blood–Brain Barrier

Daneman

Prat

2015

Cold Spring Harb Perspect Biol

2,533

1,829

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“…156 Extracellular glutamate can also increase BBB permeability in vitro 148 and in vivo through the GPCR mGluR pathways. 157 In a mouse model of CM with the murine parasite P. berghei, CNS levels of glutamate are found to be increased while glutamine is decreased at the onset of neurologic dysfunction. 158 Blockade of glutamine breakdown to glutamate using chemical inhibitors administered at the time of neurologic deterioration increased glutamine levels, reversed BBB permeability and brain swelling and rescued mice from CM.…”

Section: Metabolomicsmentioning

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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“…Neurons and glia are commonly recognized as the major targets for glutamate in the brain, but the existence of functional GluRs in cerebral vasculature has been long debated. However, the vast body of evidence accumulated over the recent years clearly demonstrates that GluRs are expressed in cerebral vascular endothelium and contribute to the endothelial functions in rats, humans, and newborn pigs [61,[84][85][86][87][88].…”

Section: Glutamate Receptors In Cerebral Vascular Endothelium and Ho-mentioning

confidence: 99%

Cerebroprotective Functions of HO-2

Parfenova¹,

Leffler²

2008

CPD

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The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via posttranslational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK Ca channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK Ca channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidantgenerating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress. KeywordsHeme oxygenase; cerebral protection; cerebrovascular disease; oxidative stress; seizures; carbon monoxide; bilirubin Vasodilator role of CO in cerebral circulation A. Vasoactive effects of exogenous CO in cerebral vesselsExperimental studies in newborn pigs conducted using in vivo and in vitro approaches demonstrate that exogenous CO is a potent vasodilator in cerebral circulation [1][2][3][4][5][6][7]. CO can be delivered to the brain as CO gas dissolved in a physiological buffer or as recently introduced CO-releasing molecules (CO-RMs) that release CO on illumination (dimanganese decacarbonyl, DMDC) or when dissolved in physiologically buffered solutions (sodium boranocarbonate, CO-RM-A1) [8,9]. In vivo, CO, DMDC and CORM-A1 applied directly to the brain surface under the cranial window at concentrations ≥10 −7 M causes dilation of pial arterioles, major resistance brain vessels that define the cerebral blood

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Neutrophil-derived Glutamate Regulates Vascular Endothelial Barrier Function

Cited by 151 publications

References 54 publications

The Blood–Brain Barrier

The Blood–Brain Barrier

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Cerebroprotective Functions of HO-2

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