Sphingosine-1-phosphate receptor 3 mediates sphingosine-1-phosphate induced release of Weibel-Palade bodies from endothelial cells

Kathinka W.E.M. Van Hooren, Léon J.A. Spijkers, Dorothee Van Breevoort, Mar Fernandez-Borja, Ruben Bierings, Jaap D. Van Buul, Astrid E. Alewijnse, Stephan L.M. Peters, Jan Voorberg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)
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Abstract

Sphingosine-1-phosphate (S1P) is an agonist for five distinct G-protein coupled receptors, that is released by platelets, mast cells, erythrocytes and endothelial cells. S1P promotes endothelial cell barrier function and induces release of endothelial cell-specific storage-organelles designated Weibel-Palade bodies (WPBs). S1P-mediated enhancement of endothelial cell barrier function is dependent on S1P receptor 1 (S1PR1) mediated signaling events that result in the activation of the small GTPase Rac1. Recently, we have reported that Rac1 regulates epinephrine-induced WPB exocytosis following its activation by phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 1 (PREX1). S1P has also been described to induce WPB exocytosis. Here, we confirm that S1P induces release of WPBs using von Willebrand factor (VWF) as a marker. Using siRNA mediated knockdown of gene expression we show that S1PR1 is not involved in S1P-mediated release of WPBs. In contrast depletion of the S1PR3 greatly reduced S1P-induced release of VWF. S1P-mediated enhancement of endothelial barrier function was not affected by S1PR3-depletion whereas it was greatly impaired in cells lacking S1PR1. The Rho kinase inhibitor Y27632 completely abrogated S1P-mediated release of VWF. Also, the calcium chelator BAPTA-AM significantly reduced S1P-induced release of VWF. Our findings indicate that S1P-induced release of haemostatic, inflammatory and angiogenic components stored within WPBs depends on the S1PR3.

Original languageEnglish
Article numbere91346
JournalPLoS ONE
Volume9
Issue number3
DOIs
Publication statusPublished - 14 Mar 2014
Externally publishedYes

Bibliographical note

Funding:
This study was supported by grants from the Landsteiner Foundation for Blood Transfusion Research (LSBR 08.19, LSBR 12.44). RB was supported by a
European Hematology Association Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation
of the manuscript.

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