Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice

Chen, Hong; Okamoto, Yasuo; Yoshioka, Kazuaki; Du, Wa; Takuwa, Noriko; Zhang, Wei; Asano, Masahide; Shibamoto, Toshishige; Takuwa, Yoh

doi:10.1016/j.jaci.2013.07.026

Cited by 48 publications

(46 citation statements)

References 44 publications

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“…When compared with control cells, cells treated with gremlin were characterized by an increased number of intercellular gaps and by the delocalization of vascular endothelial-cadherin and ZO-1 from the cell junctions to the cytoplasm ( Figure 3B). Similar to that described for VEGF-A 165 , 35 the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) prevented EC junction disruption in gremlin-stimulated cells ( Figure IV in the online-only Data Supplement). In agreement with these observations, both recombinant gremlin and VEGF-A 165 similarly affected blood vessel permeability in vivo when tested subcutaneously (s.c.) in the Miles assay 36 ( Figure 3C and Cʹ).…”

Section: Creb Mediates the Early Phases Of The Angiogenic Response Ofmentioning

confidence: 52%

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Corsini

Moroni

Ravelli

et al. 2014

ATVB

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Objective-Angiogenesis and inflammation are closely related processes. Gremlin is a novel noncanonical vascular endothelial growth factor receptor-2 (VEGFR2) ligand that induces a proangiogenic response in endothelial cells (ECs).Here, we investigated the role of the cyclic adenosine monophosphate-response element (CRE)-binding protein (CREB) in mediating the proinflammatory and proangiogenic responses of ECs to gremlin. Approach and Results-Gremlin induces a proinflammatory response in ECs, leading to reactive oxygen species and cyclic adenosine monophosphate production and the upregulation of proinflammatory molecules involved in leukocyte extravasation, including chemokine (C-C motif) ligand-2 (Ccl2) and Ccl7, chemokine (C-X-C motif) ligand-1 (Cxcl1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). Accordingly, gremlin induces the VEGFR2-dependent phosphorylation, nuclear translocation, and transactivating activity of CREB in ECs. CREB activation mediates the early phases of the angiogenic response to gremlin, including stimulation of EC motility and permeability, and leads to monocyte/macrophage adhesion to ECs and their extravasation. All these effects are inhibited by EC transfection with a dominant-negative CREB mutant or with a CREB-binding protein-CREB interaction inhibitor that competes for CREB/CRE binding. Also, both recombinant gremlin and gremlin-expressing tumor cells induce proinflammatory/proangiogenic responses in vivo that are suppressed by the anti-inflammatory drug hydrocortisone. Corsini et al CREB in Gremlin Activity 137diseases 24 and cancer. [25][26][27] Gremlin acts as a bone morphogenic protein (BMP) antagonist by binding BMP2, BMP4, and BMP7. 28 Also, gremlin stimulates EC intracellular signaling and motility in a BMP-independent manner, leading to a potent angiogenic response in vivo. 27,29 This is because of the capacity of gremlin to bind and activate VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals. 30,31 Also, gremlin interacts with heparan-sulfate proteoglycans that act as functional gremlin coreceptors in ECs, affecting its productive interaction with VEGFR2.32 However, at variance with heparin-binding VEGFs, gremlin does not interact with the coreceptor neuropilin-1. 32 Thus, gremlin is a novel proangiogenic VEGFR2 agonist distinct from canonical VEGFs.Here, we demonstrate that gremlin induces a proinflammatory response in ECs by inducing the expression of various chemokines and cell adhesion molecules, causing a VEGFR2-mediated activation of CREB. In turn, CREB activation mediates the early phases of the angiogenic response to gremlin, including stimulation of EC motility and permeability, and leads to leukocyte-adhesion to ECs and their extravasation. In keeping with these observations, gremlin and gremlin-expressing tumor cells induce a proinflammatory or proangiogenic response in vivo that is suppressed by the anti-inflammatory drug hydrocortisone. These data point to a nonredundant role of CRE...

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Section: Creb Mediates the Early Phases Of The Angiogenic Response Ofmentioning

confidence: 52%

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Corsini

Moroni

Ravelli

et al. 2014

ATVB

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“…HUVECs between passages 4 and 6 were used for all experiments. MLECs and mouse aortic smooth muscle (MASM) cells were isolated from Pik3c2a flox/flox mice and used for in vitro assays as described previously (8,32,33). HEK293T cells, MASM cells, and Caco2 cells were cultured in 10% FBS (Invitrogen Gibco)-supplemented DMEM for HEK293T and Caco2 cells (catalog no.…”

Section: Methodsmentioning

confidence: 99%

Phosphatidylinositol 3-Kinase Class II α-Isoform PI3K-C2α Is Required for Transforming Growth Factor β-induced Smad Signaling in Endothelial Cells

Aki

Yoshioka

Okamoto

et al. 2015

Journal of Biological Chemistry

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Background: TGF␤ receptor signals through Smad phosphorylation, which is dependent on endocytosis of TGF␤ receptors and the Smad anchor protein SARA localized on endosomes. Results: Class II PI3K-C2␣ is necessary for TGF␤ receptor endocytosis into SARA-containing endosomes, SARA-Smad complex formation, and Smad phosphorylation. Conclusion: PI3K-C2␣ serves endosomal TGF␤ receptor signaling. Significance: PI3K-C2␣ is a key molecule that is generally engaged in endosomal receptor signaling.

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“…The balance of S1P 1 and S1P 2 receptors in the endothelium may determine the regulation of vascular permeability by S1P (Sanchez et al 2007). More recently, Zhang et al also reported that inhibition of S1P 2 signaling dramatically decreased PLS-induced vascular permeability (Zhang et al 2013; Cui et al 2013). However, a recent study showed that S1P 2 protects mice from vascular barrier disruption elicited by either antigen challenge or PAF injection and that this protective effect of S1P 2 is mediated through suppression of anaphylaxis-associated endothelial nitric oxide synthase (eNOS) stimulation (Cui et al 2013).…”

Section: Sphingosine 1-phosphate Regulates Vascular Leak In Diseasementioning

confidence: 96%

“…More recently, Zhang et al also reported that inhibition of S1P 2 signaling dramatically decreased PLS-induced vascular permeability (Zhang et al 2013; Cui et al 2013). However, a recent study showed that S1P 2 protects mice from vascular barrier disruption elicited by either antigen challenge or PAF injection and that this protective effect of S1P 2 is mediated through suppression of anaphylaxis-associated endothelial nitric oxide synthase (eNOS) stimulation (Cui et al 2013). Thus the in vivo role of S1P 2 in inflammatory conditions such as sepsis and anaphylaxis is not yet fully understood.…”

Section: Sphingosine 1-phosphate Regulates Vascular Leak In Diseasementioning

confidence: 96%

“…At physiologically relevant concentrations, S1P is barrier protective via ligation of S1P 1 , regardless of delivery via intratracheal or intravenous routes. The activation of S1P 2 and S1P 3 receptors, however, contributes to alveolar and vascular barrier disruption, whereas the targeted deletion or silencing of S1P 2 and S1P 3 was found to be beneficial (Sammani et al 2010; Peng et al 2004; McVerry et al 2004; Zhang et al 2013; Cui et al 2013). It is also thought that S1P 2 and S1P 3 are responsible for the increased permeability that is observed after administration of higher doses of S1P or SEW2871 (Sammani et al 2010).…”

Section: Sphingosine 1-phosphate Regulates Vascular Leak In Diseasementioning

confidence: 99%

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S1P Control of Endothelial Integrity

Xiong

Hla

2014

Current Topics in Microbiology and Immunology

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Sphingosine 1-phosphate (S1P), a lipid mediator produced by sphingolipid metabolism, promotes endothelial cell spreading, vascular maturation/stabilization, and barrier function. S1P is present at high concentrations in the circulatory system, whereas in tissues its levels are low. This so-called vascular S1P gradient is essential for S1P to regulate much physiological and pathophysiological progress such as the modulation of vascular permeability. Cellular sources of S1P in blood has only recently begun to be identified. In this review, we summarize the current understanding of S1P in regulating vascular integrity. In particular, we discuss the recent discovery of the endothelium-protective functions of HDL-bound S1P which is chaperoned by apolipoprotein M.

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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

Cited by 48 publications

References 44 publications

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Phosphatidylinositol 3-Kinase Class II α-Isoform PI3K-C2α Is Required for Transforming Growth Factor β-induced Smad Signaling in Endothelial Cells

S1P Control of Endothelial Integrity

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