title: Critical role of sphingosine-1-phosphate receptor 2 (S1PR2) in acute vascular inflammation.
abstract: The endothelium, as the interface between blood and all tissues, plays a critical role in inflammation. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid, highly abundant in plasma, that potently regulates endothelial responses through interaction with its receptors (S1PRs). Here, we studied the role of S1PR2 in the regulation of the proadhesion and proinflammatory phenotype of the endothelium. By using genetic approaches and a S1PR2-specific antagonist (JTE013), we found that S1PR2 plays a key role in the permeability and inflammatory responses of the vascular endothelium during endotoxemia. Experiments with bone marrow chimeras (S1pr2(+/+) → S1pr2(+/+), S1pr2(+/+) → S1pr2(-/-), and S1pr2(-/-) → S1pr2(+/+)) indicate the critical role of S1PR2 in the stromal compartment, in the regulation of vascular permeability and vascular inflammation. In vitro, JTE013 potently inhibited tumor necrosis factor α-induced endothelial inflammation. Finally, we provide detailed mechanisms on the downstream signaling of S1PR2 in vascular inflammation that include the activation of the stress-activated protein kinase pathway that, together with the Rho-kinase nuclear factor kappa B pathway (NF-kB), are required for S1PR2-mediated endothelial inflammatory responses. Taken together, our data indicate that S1PR2 is a key regulator of the proinflammatory phenotype of the endothelium and identify S1PR2 as a novel therapeutic target for vascular disorders.
authors.affiliation: Departments of Surgery and Emergency Medicine, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Guoqi
authors.initials: G
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Gab Seok
authors.initials: GS
authors.lastname: Kim
authors.forename: Kieran
authors.initials: K
authors.lastname: Ryan
authors.forename: Shulin
authors.initials: S
authors.lastname: Lu
authors.forename: Rebekah K
authors.initials: RK
authors.lastname: O'Donnell
authors.forename: Katherine
authors.initials: K
authors.lastname: Spokes
authors.forename: Nathan
authors.initials: N
authors.lastname: Shapiro
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kluk
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Yano
authors.forename: Teresa
authors.initials: T
authors.lastname: Sanchez
mesh_terms: D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019446:Endotoxemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; C471998:JTE 013; D016328:NF-kappa B; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D048051:p38 Mitogen-Activated Protein Kinases