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Sphingosine 1‐Phosphate (S1P) Prevents Platelet Activating Factor (PAF)‐ Induced Permeability Increases by Activation of Rac‐1 Signaling in Intact Venules
Author(s) -
Zhang Gengqian,
Zhou Xueping,
He Pingnian
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.975.2
Subject(s) - microvessel , microbiology and biotechnology , chemistry , platelet activating factor , vascular permeability , biophysics , extravasation , permeability (electromagnetism) , confocal microscopy , angiogenesis , biology , endocrinology , biochemistry , immunology , membrane , cancer research
S1P has been shown to enhance endothelial (EC) barrier function in vitro and prevent hyperpermeability in vivo. Our present study aims to identify the signaling mechanisms of S1P in regulation of microvessel permeability in intact microvessels using combined permeability measurements with confocal vascular structural analysis. Microvessel permeability was determined by measuring hydraulic conductivity (Lp). Rac‐1‐dependent signaling was examined using Rac 1 inhibitor NSC23766 (NSC, 200 μM). NO was measured in DAF‐2 loaded microvessels. EC gap formation and changes in VE‐cadherin was examined with confocal microscopy using fluorescence microspheres or antibody staining. Results showed that preperfusing vessels with S1P abolished PAF‐induced gap formation and VE‐cadherin redistribution without affecting PAF‐induced increases in EC [Ca 2+ ] i and NO production. Perfusing vessels with NSC did not affect basal Lp and VE‐cadherin but abolished the inhibition of S1P on PAF‐induced Lp increases, EC gap formation, and VE‐cadherin disruption. In the presence of NSC and S1P, the peak Lp in response to PAF was restored to 7.2 ± 2 times that of the control and VE‐cadherin showed no significant difference from that with PAF alone. These results provide the first evidence in intact microvessels that S1P inhibits permeability increases by Rac1 signaling on EC AJ, which is either downstream from or independent of the initial EC Ca 2+ and NO signaling pathways. Supported by HL56237 and HL084338.