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Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/G(i)/PLC/Ca2+ signaling pathways

Title
Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/G(i)/PLC/Ca2+ signaling pathways
Authors
Yoon, CMHong, BSMoon, HGLim, SSuh, PGKim, YKChae, CBGho, YS
POSTECH Authors
Kim, YKGho, YS
Date Issued
Jan-2008
Publisher
AMER SOC HEMATOLOGY
Abstract
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 SIP 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 SIP 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 SIP-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/G(i)/phospholipase C/Ca2+ signaling pathways. Our results suggest that SIP 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.
Keywords
ENDOTHELIAL-CELL MIGRATION; LYMPHATIC VESSEL FORMATION; PROTEIN-COUPLED RECEPTORS; GROWTH-FACTOR; VEGF-C; LYSOPHOSPHATIDIC ACID; EXTRACELLULAR EXPORT; VASCULAR MATURATION; ADHESION MOLECULE-1; NITRIC-OXIDE
URI
http://oasis.postech.ac.kr/handle/2014.oak/29420
DOI
10.1182/BLOOD-2007-11-125203
ISSN
0006-4971
Article Type
Article
Citation
BLOOD, vol. 112, no. 4, page. 1129 - 1138, 2008-01
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 GHO, YONG SONG
Dept of Life Sciences
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