Sphingosine-1-phosphate prevents permeability increases via activation of endothelial sphingosine-1-phosphate receptor 1 in rat venules

Abstract

Zhang G, Xu S, Qian Y, He P. Sphingosine-1-phosphate prevents permeability increases via activation of endothelial sphingosine-1-phosphate receptor 1 in rat venules. Am J Physiol Heart Circ Physiol 299: H1494 -H1504, 2010. First published August 20, 2010 doi:10.1152/ajpheart.00462.2010.-Sphingosine-1-phosphate (S1P) has been demonstrated to enhance endothelial barrier function in vivo and in vitro. However, different S1P receptor subtypes have been indicated to play different or even opposing roles in the regulation of vascular barrier function. This study aims to differentiate the roles of endogenous endothelial S1P subtype receptors in the regulation of permeability in intact microvessels using specific receptor agonist and antagonists. Microvessel permeability was measured with hydraulic conductivity (Lp) in individually perfused rat mesenteric venules. S1P-mediated changes in endothelial intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) was measured in fura-2-loaded venules. Confocal images of fluorescent immunostaining illustrated the spatial expressions of three S1P subtype receptors (S1PR1-3) in rat venules. The application of S1P (1 M) in the presence of S1P R1-3 inhibited platelet-activating factor-or bradykinin-induced permeability increase. This S1P effect was reversed only with a selective S1PR1 antagonist, W-146, and was not affected by S1PR2 or S1PR3 antagonists JTE-013 and CAY-10444, respectively. S1PR1 was also identified as the sole receptor responsible for S1P-mediated increases in endothelial [Ca 2ϩ ]i. S1PR2 or S1PR3 antagonist alone affected neither basal Lp nor platelet-activating factor-induced permeability increase. The selective S1P R1 agonist, SEW-2871, showed similar [Ca 2ϩ ]i and permeability effect to that of S1P. These results indicate that, despite the presence of S1PR1-3 in the intact venules, only the activation of endothelial S1P R1 is responsible for the protective action of S1P on microvessel permeability and that endogenous S1PR2 or S1PR3 did not exhibit functional roles in the regulation of permeability under basal or acutely stimulated conditions. sphingosine-1-phosphate receptors; microvessel permeability; sphingosine-1-phosphate subtype receptor expression; endothelial calcium concentration AN INFLAMMATORY MEDIATOR-INDUCED increase in microvascular permeability, mainly occurring at postcapillary venules, is a critical event, resulting in edema formation, organ dysfunction, and the pathogenesis of many cardiovascular diseases. The increased microvessel permeability-associated endothelial gap formation also serves as the initiating step for the activation of platelets and leukocytes, resulting in platelet/leukocyte aggregate formation and augmented increases in microvessel permeability (12). Identifying an effective strategy to enhance endothelial barrier function and prevent permeability increases is critical for combating a variety of cardiovascular diseases.Sphingosine-1-phosphate (S1P), a biologically active lipid mediator, has been identified as an important regulat...

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