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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.
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Submitted November 20, 2007
Accepted May 27, 2008
Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways
Chang Min Yoon, Bok Sil Hong, Hyung Geun Moon, Seyoung Lim, Pann-Ghill Suh, Yoon-Keun Kim, Chi-Bom Chae, and Yong Song Gho*
Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Gyungbuk, Korea, Republic of
Institute of Biomedical Science and Technology, Konkuk University, Seoul, Korea, Republic of
* Corresponding author; email: ysgho{at}postech.ac.kr.
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 biological 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, 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.
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