Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice
- PMID: 24021572
- DOI: 10.1016/j.jaci.2013.07.026
Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice
Abstract
Background: Sphingosine-1-phosphate receptor 2 (S1P(2)) is expressed in vascular endothelial cells (ECs). However, the role of S1P(2) in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P(2) inhibits Akt, an activating kinase of eNOS.
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.
Keywords: AJ; Adherens junction; Cyclic guanosine monophosphate; EC; Endothelial cell; Endothelial nitric oxide synthase; L-NAME; MLEC; Mouse lung endothelial cell; NO; Nitric oxide; Nω-L-nitro-arginine methyl ester; OVA; Ovalbumin; PAF; PI3K; PTEN; Phosphatase and tensin homolog deleted from chromosome 10; Phosphatidylinositol 3-kinase; Platelet-activating factor; S1P; S1P(2); Sphingosine-1-phosphate; VE-cadherin; VEGF; Vascular endothelial growth factor A; WT; Wild-type; adherens junction; anaphylaxis; cGMP; eNOS; endothelial nitric oxide synthase; nitric oxide; nitrosylation; vascular permeability; β-catenin.
Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
Similar articles
-
S-nitrosylation of beta-catenin by eNOS-derived NO promotes VEGF-induced endothelial cell permeability.Mol Cell. 2010 Aug 13;39(3):468-76. doi: 10.1016/j.molcel.2010.07.013. Mol Cell. 2010. PMID: 20705246
-
Sphingosine-1-phosphate receptor 2 mediates endothelial cells dysfunction by PI3K-Akt pathway under high glucose condition.Eur J Pharmacol. 2016 Apr 5;776:19-25. doi: 10.1016/j.ejphar.2016.02.056. Epub 2016 Feb 26. Eur J Pharmacol. 2016. PMID: 26921757
-
Protein kinase CK2/PTEN pathway plays a key role in platelet-activating factor-mediated murine anaphylactic shock.J Immunol. 2011 Jun 1;186(11):6625-32. doi: 10.4049/jimmunol.1100007. Epub 2011 Apr 29. J Immunol. 2011. PMID: 21531890
-
S1P and eNOS regulation.Biochim Biophys Acta. 2008 Sep;1781(9):489-95. doi: 10.1016/j.bbalip.2008.06.008. Epub 2008 Jun 27. Biochim Biophys Acta. 2008. PMID: 18638569 Review.
-
Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors.Drug News Perspect. 2004 Jul-Aug;17(6):365-82. doi: 10.1358/dnp.2004.17.6.829028. Drug News Perspect. 2004. PMID: 15334188 Review.
Cited by
-
The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer's Disease and Other Neurodegenerative Disorders.Mol Neurobiol. 2019 Aug;56(8):5436-5455. doi: 10.1007/s12035-018-1448-3. Epub 2019 Jan 5. Mol Neurobiol. 2019. PMID: 30612333 Free PMC article. Review.
-
Sphingosine-1-phosphate receptor-2 facilitates pulmonary fibrosis through potentiating IL-13 pathway in macrophages.PLoS One. 2018 May 21;13(5):e0197604. doi: 10.1371/journal.pone.0197604. eCollection 2018. PLoS One. 2018. PMID: 29782549 Free PMC article.
-
Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production.J Allergy Clin Immunol. 2015 Mar;135(3):729-36.e5. doi: 10.1016/j.jaci.2014.11.003. Epub 2014 Dec 29. J Allergy Clin Immunol. 2015. PMID: 25553642 Free PMC article.
-
Critical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke.Nat Commun. 2015 Aug 5;6:7893. doi: 10.1038/ncomms8893. Nat Commun. 2015. PMID: 26243335 Free PMC article.
-
Endothelial S1pr2 regulates post-ischemic angiogenesis via AKT/eNOS signaling pathway.Theranostics. 2022 Jul 4;12(11):5172-5188. doi: 10.7150/thno.71585. eCollection 2022. Theranostics. 2022. PMID: 35836816 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials