title: Sphingosine-1-phosphate induces VEGF-C expression through a MMP-2/FGF-1/FGFR-1-dependent pathway in endothelial cells in vitro.
abstract: OBJECTIVE
  To investigate whether sphingosine-1-phosphate (S1P), a potent angiogenic factor, induced vascular endothelial growth factor-C (VEGF-C) expression in endothelial cells in vitro and to examine its underlying mechanisms.
  
  
  METHODS
  Human umbilical vein endothelial cells (HUVECs) were examined. VEGF-C mRNA expression in the cells was assessed using real-time PCR. VEGF-C protein and FGFR-1 phosphorylation in the cells were measured with ELISA. RNA interference was used to downregulate the expression of matrix metalloproteinase-2 (MMP-2), fibroblast growth factor-1 (FGF-1) and FGF receptor-1 (FGFR-1).
  
  
  RESULTS
  Incubation of HUVECs with S1P (1, 5, and 10 μmol/L) significantly increased VEGF-C expression. The effect was blocked by pretreatment with the MMP inhibitor GM6001 or the FGFR inhibitor SU5402, but not the EGFR inhibitor AG1478. The effect was also blocked in HUVECs that were transfected with FGFR-1 or MMP-2 siRNA. Furthermore, incubation of HUVECs with S1P (5 μmol/L) significantly increased FGFR-1 phosphorylation, which was blocked by GM6001. Moreover, knockdown of FGF-1, not FGF-2, in HUVECs with siRNAs, blocked S1P-induced VEGF-C expression.
  
  
  CONCLUSIONS
  S1P induces VEGF-C expression through a MMP-2/ FGF-1/FGFR-1-dependent pathway in HUVECs.
authors: Institute of Zoology, National Taiwan University, Taipei, Taiwan, China.
authors: Chi-hao
authors: CH
authors: Chang
authors: Yuan-li
authors: YL
authors: Huang
authors: Ming-kwang
authors: MK
authors: Shyu
authors: Shee-uan
authors: SU
authors: Chen
authors: Chih-hsin
authors: CH
authors: Lin
authors: Tsai-kai
authors: TK
authors: Ju
authors: JenHer
authors: J
authors: Lu
authors: Hsinyu
authors: H
authors: Lee
mesh_terms: D018929:Cell Culture Techniques; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology* / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*
chemical_list: D008246:Lysophospholipids; D034741:RNA, Small Interfering; D042582:Vascular Endothelial Growth Factor C; D016220:Fibroblast Growth Factor 1; C060506:sphingosine 1-phosphate; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D013110:Sphingosine
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