vascular inflammation Critical role of sphingosine-1-phosphate receptor 2 (S1PR2) in acute

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, which potently regulates endothelial responses through the interaction with its receptors (S1PR). Here, we aimed to study the role of S1PR2 in the regulation of the proadhesion and proinflammatory phenotype of the endothelium. 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 +/+ to S1pr2 +/+ , S1pr2 +/+ to S1pr2 -/- and S1pr2 -/- to 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 TNF-α-induced endothelial inflammation. Lastly, we provide detailed mechanisms on the downstream signaling of S1PR2 in vascular inflammation that include the activation of the stress activated protein kinase pathway, which, together with the Rho-Kinase-Nuclear Factor Kappa B pathway, 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. From bloodjournal.hematologylibrary.org at Harvard Libraries on June 14, 2013. For personal use only.