Lysophosphatidic Acid Increases Tight Junction Permeability in Cultured Brain Endothelial Cells

Schulze, C.; Smales, Caroline; Rubin, Lee; Staddon, James M.

doi:10.1046/j.1471-4159.1997.68030991.x

Cited by 165 publications

(89 citation statements)

References 2 publications

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“…12,28 In the case of permeability, most studies including the present study support an increase in vascular leakage after LPA exposure. 12,16 In cultured BMECs, LPA exposure has been associated with increases in permeability.…”

Section: Studies By Yanagida K Et Alsupporting

confidence: 61%

“…The effects of LPA on vascular permeability are a topic of considerable debate with some studies reporting a decrease in endothelial cell permeability after LPA exposure, 14,15 whereas others support an increase in vascular leakage after LPA exposure. 11,12,16 Studies of LPA on brain microvessel endothelial cell permeability support an enhancement of permeability with decrease in transcellular electrical resistance and increases in flux of vascular markers observed in primary cultured brain endothelial cell preparations. 12,16 More recent studies indicate increased permeability after localized application of LPA to the cerebral microvasculature.…”

Section: Introductionmentioning

confidence: 84%

“…12,16 In cultured BMECs, LPA exposure has been associated with increases in permeability. 11,12 However, there are contradictory reports of LPA-induced reductions in endothelial cell permeability (i.e., barrier-enhancing properties). 15 The conflicting reports regarding LPA-induced permeability could be dependent on a number of factors including differences in vascular bed, species, or the profile of LPA receptors expressed.…”

Section: Studies By Yanagida K Et Almentioning

confidence: 99%

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Rapid and Reversible Enhancement of Blood–Brain Barrier Permeability Using Lysophosphatidic Acid

Savant

Toews

et al. 2013

J Cereb Blood Flow Metab

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The present study characterizes the effects of lysophosphatidic acid (LPA) on blood-brain barrier (BBB) permeability focusing specifically on the time of onset, duration, and magnitude of LPA-induced changes in cerebrovascular permeability in the mouse using both magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIFR). Furthermore, potential application of LPA for enhanced drug delivery to the brain was also examined by measuring the brain accumulation of radiolabeled methotrexate. Exposure of primary cultured brain microvessel endothelial cells (BMECs) to LPA produced concentration-dependent increases in permeability that were completely abolished by clostridium toxin B. Administration of LPA disrupted BBB integrity and enhanced the permeability of small molecular weight marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRdye800cwPEG, and the P-glycoprotein efflux transporter probe, Rhodamine 800 (R800). The increase in BBB permeability occurred within 3 minutes after LPA injection and barrier integrity was restored within 20 minutes. A decreased response to LPA on large macromolecule BBB permeability was observed after repeated administration. The administration of LPA also resulted in 20-fold enhancement of radiolabeled methotrexate in the brain. These studies indicate that administration of LPA in combination with therapeutic agents may increase drug delivery to the brain.

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Section: Studies By Yanagida K Et Alsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 84%

Section: Studies By Yanagida K Et Almentioning

confidence: 99%

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Rapid and Reversible Enhancement of Blood–Brain Barrier Permeability Using Lysophosphatidic Acid

Savant

Toews

et al. 2013

J Cereb Blood Flow Metab

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“…It has been reported that the 18:1 LPA-induced endothelial activation involves a morphological change in the cell from a cobblestone-like shape to a round one, resulting in a sparse cell-to-cell contact. 12,13 Such 18:1 LPA-induced endothelial cell activation might enable the incorporation of 18:1 LPA into the vascular wall in vivo. 18:1 LPA also activates the expression of proinflammatory genes in cultured endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Vascular Remodeling Induced by Naturally Occurring Unsaturated Lysophosphatidic Acid In Vivo

et al. 2003

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Background-We previously identified unsaturated (16:1, 18:1, and 18:2) but not saturated (12:0, 14:0, 16:0, and 18:0) lysophosphatidic acids (LPAs) as potent factors for vascular smooth muscle cell (VSMC) dedifferentiation. Unsaturated LPAs strongly induce VSMC dedifferentiation via the coordinated activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK), resulting in the proliferation and migration of dedifferentiated VSMCs. Here, we investigated the effects of 18:1 and 18:0 LPAs (as representative unsaturated and saturated LPAs, respectively) on the vasculature in vivo. Methods and Results-Rat common carotid arteries (CCAs) were treated transiently with 18:1 or 18:0 LPA and then examined by histological and biochemical analyses.

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“…LPA and LPA receptors are enriched in the brain (Das and Hajra, 1989;van der Bend et al, 1992;Thomson et al, 1994;Hecht et al, 1996;An et al, 1997). LPA has multiple effects on cells of the brain, including LPA-mediated stimulation of neurite retraction of neuroblastoma and PC 12 cells, stimulation of astrocyte proliferation, and increased permeability of cultured brain endothelial cells (Tigyi and Miledi, 1992;Jalink et al, 1993;Schulze et al, 1997). The expression of a newly cloned LPA receptor is developmentally regulated in the brain, and expression is markedly increased in association with embryonic programmed cell death of neurons (Hecht et al, 1996).…”

mentioning

confidence: 99%

Lysophosphatidic Acid Induces Necrosis and Apoptosis in Hippocampal Neurons

Holtsberg¹,

Steiner²,

Keller³

et al. 1998

Journal of Neurochemistry

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A diverse body of evidence indicates a role for the lipid biomediator lysophosphatidic acid (LPA) in the CNS. This study identifies and characterizes the induction of neuronal death by LPA. Treatment of cultured hippocampal neurons from embryonic rat brains with 50~eM LPA resulted in neuronal necrosis, as determined morphologically and by the release of lactate dehydrogenase. A concentration of LPA as low as 10~iMled to the release of lactate dehydrogenase. In contrast, treatment of neurons with 0.1 or 1.0 j.tM LPA resulted in apoptosis, as determined by chromatin condensation. In addition, neuronal death induced by 1 ,aM LPA was characterized as apoptotic on the basis of terminal dUTP nick end-labeling (TUNEL) staining, externalization of phosphatidylserme, and protection against chromatin condensation, TU N EL staining, and phosphatidylserine externalization by treatment with N-benzyloxycarbonyl-Val-Ala-Aspfluoromethyl ketone, a broad-spectrum inhibitor of caspases, i.e., members of the interleukin-1/3 converting enzyme family. Studies with antagonists of ionotropic glutamate receptors did not indicate a significant role for these receptors in apoptosis induced by 1 1iM LPA. LPA (1 1iM) also induced a decrease in mitochondrial membrane potential. Moreover, pretreatment of neurons with cyclosporin A protected against the LPA-induced decrease in mitochondrial membrane potential and neuronal apoptosis. Thus, LPA, at pathophysiological levels, can induce neuronal apoptosis and could thereby participate in neurodegenerative disorders. Key Words: Lysophosphatidic acid-Apoptosis-Neurons-Mitochondrial membrane potential -Cyclosporin A.

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Lysophosphatidic Acid Increases Tight Junction Permeability in Cultured Brain Endothelial Cells

Abstract: Brain capillary endothelial cells

Cited by 165 publications

References 2 publications

Rapid and Reversible Enhancement of Blood–Brain Barrier Permeability Using Lysophosphatidic Acid

Rapid and Reversible Enhancement of Blood–Brain Barrier Permeability Using Lysophosphatidic Acid

Vascular Remodeling Induced by Naturally Occurring Unsaturated Lysophosphatidic Acid In Vivo

Lysophosphatidic Acid Induces Necrosis and Apoptosis in Hippocampal Neurons

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