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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1129-1138. Prepublished online as a Blood First Edition Paper on June 9, 2008; DOI 10.1182/blood-2007-11-125203. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-11-125203v1 112/4/1129    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yoon, C. M. Articles by Gho, Y. S. Search for Related Content PubMed PubMed Citation Articles by Yoon, C. M. Articles by Gho, Y. S. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways Chang Min Yoon1, Bok Sil Hong1, Hyung Geun Moon1, Seyoung Lim1, Pann-Ghill Suh1, Yoon-Keun Kim1, Chi-Bom Chae2, and Yong Song Gho1 1 Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea; and 2 Institute of Biomedical Science and Technology, Konkuk University, Seoul, Republic of Korea The lymphatic system plays pivotal roles in mediating tissue fluid homeostasis and immunity, and excessive lymphatic vessel formation is implicated in many pathological conditions, which include inflammation and tumor metastasis. However, the molecular mechanisms that regulate lymphatic vessel formation remain poorly characterized. Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that is implicated in a variety of biologic processes such as inflammatory responses and angiogenesis. Here, we first report that S1P acts as a lymphangiogenic mediator. S1P induced migration, capillary-like tube formation, and intracellular Ca2+ mobilization, but not proliferation, in human lymphatic endothelial cells (HLECs) in vitro. Moreover, a Matrigel plug assay demonstrated that S1P promoted the outgrowth of new lymphatic vessels in vivo. HLECs expressed S1P1 and S1P3, and both RNA interference–mediated down-regulation of S1P1 and an S1P1 antagonist significantly blocked S1P-mediated lymphangiogenesis. Furthermore, pertussis toxin, U73122 [GenBank] , and BAPTA-AM efficiently blocked S1P-induced in vitro lymphangiogenesis and intracellular Ca2+ mobilization of HLECs, indicating that S1P promotes lymphangiogenesis by stimulating S1P1/Gi/phospholipase C/Ca2+ signaling pathways. Our results suggest that S1P is the first lymphangiogenic bioactive lipid to be identified, and that S1P and its receptors might serve as new therapeutic targets against inflammatory diseases and lymphatic metastasis in tumors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W. P. Dunworth and K. M. Caron G Protein-Coupled Receptors as Potential Drug Targets for Lymphangiogenesis and Lymphatic Vascular Diseases Arterioscler Thromb Vasc Biol, May 1, 2009; 29(5): 650 - 656. [Abstract] [Full Text] [PDF] F. Spinella, E. Garrafa, V. Di Castro, L. Rosano, M. R. Nicotra, A. Caruso, P. G. Natali, and A. Bagnato Endothelin-1 Stimulates Lymphatic Endothelial Cells and Lymphatic Vessels to Grow and Invade Cancer Res., March 15, 2009; 69(6): 2669 - 2676. [Abstract] [Full Text] [PDF] C. Jang, Y. J. Koh, N. K. Lim, H. J. Kang, D. H. Kim, S. K. Park, G. M. Lee, C. J. Jeon, and G. Y. Koh Angiopoietin-2 Exocytosis Is Stimulated by Sphingosine-1-Phosphate in Human Blood and Lymphatic Endothelial Cells Arterioscler Thromb Vasc Biol, March 1, 2009; 29(3): 401 - 407. [Abstract] [Full Text] [PDF] P. J. Gonzalez-Cabrera, E. Jo, M. G. Sanna, S. Brown, N. Leaf, D. Marsolais, M.-T. Schaeffer, J. Chapman, M. Cameron, M. Guerrero, et al. Full Pharmacological Efficacy of a Novel S1P1 Agonist That Does Not Require S1P-Like Headgroup Interactions Mol. Pharmacol., November 1, 2008; 74(5): 1308 - 1318. [Abstract] [Full Text] [PDF]

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