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

Author(s)
Yoon, Chang MinHong, Bok SilMoon, Hyung GeunLim, SeyoungSuh, Pann-GhillKim, Yoon-KeunChae, Chi-BomGho, Yong Song
Issued Date
2008-08
DOI
10.1182/blood-2007-11-125203
URI
https://scholarworks.unist.ac.kr/handle/201301/5656
Fulltext
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=51649099579
Citation
BLOOD, v.112, no.4, pp.1129 - 1138
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 S1P acts as a lymphangiogenic mediator. S1P induced migration, capillarylike 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 SIP-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.
Publisher
AMER SOC HEMATOLOGY
ISSN
0006-4971
Keyword
ENDOTHELIAL-CELL MIGRATIONLYMPHATIC VESSEL FORMATIONPROTEIN-COUPLED RECEPTORSGROWTH-FACTORVEGF-CLYSOPHOSPHATIDIC ACIDEXTRACELLULAR EXPORTVASCULAR MATURATIONADHESION MOLECULE-1NITRIC-OXIDE

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