Brain microvessel endothelin type A receptors are coupled to ceramide production

Collado, M. Pilar; Latorre, Eduardo; Fernández, Inmaculada; Aragonés, M.D.; Catalán, Rosa

doi:10.1016/s0006-291x(03)00927-6

Cited by 7 publications

(5 citation statements)

References 24 publications

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“…Isolated brain microvessels, however, were shown to generate ceramides in reaction to endothelin‐1 which is involved in regulating BBB permeability (Collado et al . ). Ceramides are well‐acknowledged to be proinflammatory as they are triggered by several cytokines, interleukins, or platelet‐activating factor during inflammation.…”

Section: Discussionmentioning

confidence: 97%

Alteration of sphingolipid metabolism as a putative mechanism underlying LPS‐induced BBB disruption

Vutukuri

Brunkhorst

Kestner

et al. 2017

Journal of Neurochemistry

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Septic encephalopathy with confusion and agitation occurs early during sepsis and contributes to the severity of the disease. A decrease in the sphingosine-1-phosphate (S1P) blood levels has been shown in patients and in animal models of sepsis. The lipid mediator S1P is known to be involved in endothelial barrier function in a context-dependent manner. We utilized lipopolysaccharide (LPS)-injected mice as a model for septic encephalopathy and first performed tracer permeability assays to assess the blood-brain barrier (BBB) breakdown in vivo. At time points corresponding to the BBB breakdown post LPS injection, we aimed to characterize the regulation of the sphingolipid signaling pathway at the BBB during sepsis. We measured sphingolipid concentrations in blood, in mouse brain microvessels (MBMVs), and brain tissue. We also analyzed the expression of S1P receptors, transporters, and metabolizing enzymes in MBMVs and brain tissue. Primary mouse brain microvascular endothelial cells (MBMECs) were isolated to evaluate the effects of LPS on transendothelial electrical resistance (TEER) as a measure of permeability in vitro. We observed a relevant decrease in S1P levels after LPS injection in all three compartments (blood, MBMVs, brain tissue) that was accompanied by an increased expression of the S1P receptor type 1 and of sphingosine kinase 1 on one hand and of the S1P degrading enzymes lipid phosphate phosphatase 1 (LPP1) and S1P phosphatase 1 on the other hand, as well as a down-regulation of sphingosine kinase 2. Application of LPS to a monolayer of primary MBMECs did not alter TEER, but serum from LPS-treated mice lead to a breakdown of the barrier compared to serum from vehicle-treated mice. We observed profound alterations of the sphingolipid metabolism at the BBB after LPS injection that point toward a therapeutic potential of drugs interfering with this pathway as novel approach for the detrimental overwhelming immune response in sepsis. Read the Editorial Highlight for this article on page 115. Cover Image for this Issue: doi. 10.1111/jnc.14161.

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Section: Discussionmentioning

confidence: 97%

Alteration of sphingolipid metabolism as a putative mechanism underlying LPS‐induced BBB disruption

Vutukuri

Brunkhorst

Kestner

et al. 2017

Journal of Neurochemistry

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“…However, this does not guarantee that BBB function and integrity are preserved. Isolated brain microvessels have been successfully used for the identification of mechanisms and biochemical signals that play a role in regulating BBB functions106–109 in health and diseased conditions (e.g., brain tumors) 110. The major advantages of using isolated brain microvessels include the maintenance of the structural and cellular characteristics and properties (cell differentiation) in ex vivo experimentations.…”

Section: Isolated Brain Microvesselsmentioning

confidence: 99%

In Vitro Blood–Brain Barrier Models: Current and Perspective Technologies

Naik

Cucullo

2012

Journal of Pharmaceutical Sciences

252

188

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Even in the 21st century, studies aimed at characterizing the pathological paradigms associated with the development and progression of central nervous system diseases are primarily performed in laboratory animals. However, limited translational significance, high cost, and labor to develop the appropriate model (e.g., transgenic or inbred strains) have favored parallel in vitro approaches. In vitro models are of particular interest for cerebrovascular studies of the blood–brain barrier (BBB), which plays a critical role in maintaining the brain homeostasis and neuronal functions. Because the BBB dynamically responds to many events associated with rheological and systemic impairments (e.g., hypoperfusion), including the exposure of potentially harmful xenobiotics, the development of more sophisticated artificial systems capable of replicating the vascular properties of the brain microcapillaries are becoming a major focus in basic, translational, and pharmaceutical research. In vitro BBB models are valuable and easy to use supporting tools that can precede and complement animal and human studies. In this article, we provide a detailed review and analysis of currently available in vitro BBB models ranging from static culture systems to the most advanced flow-based and three-dimensional coculture apparatus. We also discuss recent and perspective developments in this ever expanding research field.

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“…This study showed that 2-AG counteracts calcium mobilization and cytoskeleton rearrangements induced by ET-1 suggesting that the crosstalk between these two neurotransmitter systems might be relevant for the regulation of cerebral capillary and microvascular function. In addition, treatment of brain microvessels with ET-1 decreases sphyngomyelin and ethanolamine plasmalogen levels, increases ceramides levels and evokes platelet activating factor (PAF) production via ET A receptors [22,23]. In human brain-derived endothelial cells, ET-1 induces interleukin-8 production via the stimulation of ET A receptors and by signalling pathways involving the activation of protein kinases and protein tyrosine kinases [193].…”

Section: Endotheliummentioning

confidence: 99%

Pharmacology and Physiopathology of the Brain Endothelin System: An Overview

Schinelli¹

2006

CMC

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The endothelin system, consisting of three peptides, two peptidases and two G-protein coupled receptors, is widely expressed in the brain cell types and brain-derived tumor cell lines. The stimulation of endothelin receptors elicits a variety of short- and long-term changes at cellular level but the effects of the pharmacological modulation of the endothelin system in brain physiology and pathophysiology are, at the present time, poorly understood. Altered expression of endothelins (ETs) in reactive astrocytes has been observed in many pathological conditions of the human brain, such as infarcts, lacunae, traumatic conditions, Alzheimer's disease and inflammatory diseases of the brain. In addition, recent studies have shown that endothelin antagonists might inhibit growth and induce cell death in human melanoma cells in vitro and in vivo, and have emphasized a possible role of endothelin peptides as autocrine or paracrine factor in the proliferation and dissemination of tumor cell lines. Given the fact that brain cell and a variety of brain tumor cell lines express functional endothelin receptors, further studies are warranted to demonstrate a possible therapeutic role of endothelin agonists and antagonist in the pharmacological treatment of brain-related diseases and brain tumors.

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Brain microvessel endothelin type A receptors are coupled to ceramide production

Cited by 7 publications

References 24 publications

Alteration of sphingolipid metabolism as a putative mechanism underlying LPS‐induced BBB disruption

Alteration of sphingolipid metabolism as a putative mechanism underlying LPS‐induced BBB disruption

In Vitro Blood–Brain Barrier Models: Current and Perspective Technologies

Pharmacology and Physiopathology of the Brain Endothelin System: An Overview

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