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Am J Physiol Heart Circ Physiol 296: H33-H42, 2009. First published November 14, 2008; doi:10.1152/ajpheart.00097.2008
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TRANSLATIONAL PHYSIOLOGY

Balance of S1P1 and S1P2 signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature

Jen-Fu Lee,1 Sharon Gordon,2 Rosendo Estrada,1 Lichun Wang,1 Deanna L. Siow,3 Binks W. Wattenberg,3,4,5 David Lominadze,2,* and Menq-Jer Lee1,6,*

1Gheens Center on Aging and Departments of 2Physiology and Biophysics, 3Biochemistry and Molecular Biology, 4Medicine, 5Pharmacology and Toxicology, and 6Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, Kentucky

Submitted 30 January 2008 ; accepted in final form 3 November 2008

Sphingosine-1-phosphate (S1P) regulates various molecular and cellular events in cultured endothelial cells, such as cytoskeletal restructuring, cell-extracellular matrix interactions, and intercellular junction interactions. We utilized the venular leakage model of the cremaster muscle vascular bed in Sprague-Dawley rats to investigate the role of S1P signaling in regulation of microvascular permeability. S1P signaling is mediated by the S1P family of G protein-coupled receptors (S1P1-5 receptors). S1P1 and S1P2 receptors, which transduce stimulatory and inhibitory signaling, respectively, are expressed in the endothelium of the cremaster muscle vasculature. S1P administration alone via the carotid artery was unable to protect against histamine-induced venular leakage of the cremaster muscle vascular bed in Sprague-Dawley rats. However, activation of S1P1-mediated signaling by SEW2871 and FTY720, two agonists of S1P1, significantly inhibited histamine-induced microvascular leakage. Treatment with VPC 23019 to antagonize S1P1-regulated signaling greatly potentiated histamine-induced venular leakage. After inhibition of S1P2 signaling by JTE-013, a specific antagonist of S1P2, S1P was able to protect microvascular permeability in vivo. Moreover, endothelial tight junctions and barrier function were regulated by S1P1- and S1P2-mediated signaling in a concerted manner in cultured endothelial cells. These data suggest that the balance between S1P1 and S1P2 signaling regulates the homeostasis of microvascular permeability in the peripheral circulation and, thus, may affect total peripheral vascular resistance.

spingosine-1-phosphate receptor subtypes; vascular integrity; signal transduction


Addresses for reprint requests and other correspondence: D. Lominadze, Dept. of Physiology and Biophysics, School of Medicine, Univ. of Louisville, 580 S. Preston St., Louisville, KY 40202 (e-mail: dglomi01{at}louisville.edu); M. J. Lee, Dept. of Microbiology and Immunology, School of Medicine, Univ. of Louisville, 580 S. Preston St., Louisville, KY 40202 (e-mail: menqjer.lee{at}louisville.edu)






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