Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways.
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.
Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
Chang Min
CM
Yoon
Bok Sil
BS
Hong
Hyung Geun
HG
Moon
Seyoung
S
Lim
Pann-Ghill
PG
Suh
Yoon-Keun
YK
Kim
Chi-Bom
CB
Chae
Yong Song
YS
Gho
D020013:Calcium Signaling; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology*; D004729:Endothelium, Lymphatic; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D042583:Lymphangiogenesis; D008246:Lysophospholipids / Q000502:physiology*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism
D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D010738:Type C Phospholipases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D013110:Sphingosine