Abstract | BACKGROUND: OBJECTIVE: We tested the hypothesis that endothelial S1P(2) might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. METHODS: Mice deficient in S1P(2) and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. RESULTS: S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2-null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr-null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2-null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2-null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2-deficient ECs showed more severe disassembly of adherens junctions with augmented S-nitrosylation of β- catenin in response to PAF, which was restored by pharmacologic eNOS blockade. CONCLUSION: S1P(2) diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P(2) agonists as novel therapeutic agents for anaphylaxis.
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Authors | Hong Cui, Yasuo Okamoto, Kazuaki Yoshioka, Wa Du, Noriko Takuwa, Wei Zhang, Masahide Asano, Toshishige Shibamoto, Yoh Takuwa |
Journal | The Journal of allergy and clinical immunology
(J Allergy Clin Immunol)
Vol. 132
Issue 5
Pg. 1205-1214.e9
(Nov 2013)
ISSN: 1097-6825 [Electronic] United States |
PMID | 24021572
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved. |
Chemical References |
- Platelet Activating Factor
- Receptors, Lysosphingolipid
- beta Catenin
- Nitric Oxide Synthase Type III
- Proto-Oncogene Proteins c-akt
- NG-Nitroarginine Methyl Ester
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Topics |
- Adherens Junctions
(metabolism)
- Anaphylaxis
(genetics, metabolism, mortality)
- Animals
- Aorta
(immunology, metabolism)
- Capillary Permeability
(genetics, immunology)
- Disease Models, Animal
- Endothelial Cells
(drug effects, metabolism)
- Enzyme Activation
- Gene Deletion
- Lung
(immunology, metabolism)
- Mice
- Mice, Knockout
- NG-Nitroarginine Methyl Ester
(pharmacology)
- Nitric Oxide Synthase Type III
(antagonists & inhibitors, genetics, metabolism)
- Platelet Activating Factor
(pharmacology)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Receptors, Lysosphingolipid
(genetics, metabolism)
- Signal Transduction
- beta Catenin
(metabolism)
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