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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1312.)
© 2007 American Heart Association, Inc.

Vascular Biology

Induction of Vascular Permeability by the Sphingosine-1-Phosphate Receptor–2 (S1P2R) and its Downstream Effectors ROCK and PTEN

Teresa Sanchez; Athanasia Skoura; Ming Tao Wu; Brian Casserly; Elizabeth O. Harrington; Timothy Hla

From the Center for Vascular Biology (T.S., A.S., M.T.W., T.H.), Department of Cell Biology, University of Connecticut Health Center, Farmington, Conn; and the Vascular Research Laboratory (B.C., E.O.H.), Providence Veterans Affairs Medical Center, Department of Medicine, Brown Medical School, Providence, RI.

Correspondence to Teresa Sanchez or Timothy Hla, Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030-3501. E-mail sanchez{at}neuron.uchc.edu or hla@nso2.uchc.edu

Objectives— S1P acts via the S1PR family of G protein–coupled receptors to regulate a variety of physiological responses. Whereas S1P1R activates G_i- and PI-3-kinase–dependent signals to inhibit vascular permeability, the related S1P2R inhibits the PI-3-kinase pathway by coupling to the Rho-dependent activation of the PTEN phosphatase. However, cellular consequences of S1P2R signaling in the vascular cells are not well understood.

Methods and Results— Selective signaling of the S1P2R was achieved by adenoviral-mediated expression in endothelial cells. Secondly, endogenously expressed S1P2R was blocked by the specific pharmacological antagonist JTE013. Activation of S1P2R in endothelial cells resulted in Rho-ROCK– and PTEN-dependent disruption of adherens junctions, stimulation of stress fibers, and increased paracellular permeability. JTE013 treatment of naive endothelial cells potentiated the S1P1R-dependent effects such as formation of cortical actin, blockade of stress fibers, stimulation of adherens junction assembly, and improved barrier integrity. This observation was extended to the in vivo model of vascular permeability in the rat lung: the S1P2R antagonist JTE013 significantly inhibited H₂O₂-induced permeability in the rat lung perfused model.

Conclusions— S1P2R activation in endothelial cells increases vascular permeability. The balance of S1P1 and S1P2 receptors in the endothelium may determine the regulation of vascular permeability by S1P.

We tested the hypothesis that S1P2R signaling via Rho–ROCK–PTEN pathway is a critical modulator of vascular permeability. Our results show that activation of S1P2R in endothelial cells results in Rho-, p160-Rho–associated kinase (ROCK)- and PTEN-dependent disruption of endothelial cell–cell junctions, profound modulation of actin cytoskeletal dynamics, and increased paracellular permeability.

Key Words: sphingosine-1-phosphate • Rho • ROCK • PTEN • permeability

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