Article

Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways.

Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
Blood (impact factor: 9.9). 07/2008; 112(4):1129-38. DOI:10.1182/blood-2007-11-125203 pp.1129-38
Source: PubMed

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, capillary-like tube formation, and intracellular Ca(2+) 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 Ca(2+) mobilization of HLECs, indicating that S1P promotes lymphangiogenesis by stimulating S1P1/G(i)/phospholipase C/Ca(2+) 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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Keywords

excessive lymphatic vessel formation
 
first lymphangiogenic bioactive lipid
 
human lymphatic endothelial cells
 
inflammatory responses
 
intracellular Ca(2+)
 
lymphangiogenic mediator
 
Matrigel plug assay
 
mediating tissue fluid homeostasis
 
molecular mechanisms
 
new lymphatic vessels
 
new therapeutic targets
 
potent bioactive lipid
 
regulate lymphatic vessel formation
 
RNA interference-mediated down-regulation
 
S1P acts
 
S1P induced migration
 
S1P promotes lymphangiogenesis
 
S1P-mediated lymphangiogenesis
 
S1P1 antagonist
 
vitro lymphangiogenesis