title: Sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis is involved in liver fibrosis-associated angiogenesis.
abstract: OBJECTIVE
  Sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) axis is involved in multiple biological processes, including liver fibrosis. Angiogenesis is an important pathophysiological process closely associated with liver fibrosis; however, the functional role of SphK/S1P/S1PR in this process remains incompletely defined.
  
  
  METHODS
  Bile duct ligation or carbon tetrachloride was used to induce liver fibrosis in mice. Human fibrotic samples were obtained from livers of patients undergoing liver transplantation. S1P levels in the liver were examined by HPLC. Expression of angiogenic markers, including angiopoietin 1, CD31, vascular cell adhesion molecule-1, and von Willebrand factor, was characterized by immunofluorescence, real-time RT-PCR, and Western blot in the fibrotic liver and primary mouse hepatic stellate cells (HSCs). SphK inhibitor (SKI) or S1PR antagonists were administered intraperitoneally in mice.
  
  
  RESULTS
  S1P levels in the liver were closely correlated with mRNA expression of angiogenic markers. Ang1 is expressed in activated HSCs of the fibrotic liver and in primary HSCs. In HSCs, by using specific antagonists or siRNAs, we demonstrated S1P stimulation induced Ang1 expression via S1PR1 and S1PR3. In vivo, S1P reduction by SKI inhibited angiogenesis in fibrotic mice. Furthermore, S1PR1/3 antagonist significantly blocked upregulation of angiogenic markers in the injured liver, and attenuated the extent of liver fibrosis, while S1PR2 antagonist had no effect on angiogenesis, supporting the key role of S1PR1 and S1PR3 in angiogenesis underlying liver fibrosis process.
  
  
  CONCLUSIONS
  SphK1/S1P/S1PR1/3 axis plays a crucial role in the angiogenic process required for fibrosis development, which may represent an effective therapeutic strategy for liver fibrosis.
authors: Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
authors: Le
authors: L
authors: Yang
authors: Shi
authors: S
authors: Yue
authors: Lin
authors: L
authors: Yang
authors: Xin
authors: X
authors: Liu
authors: Zhen
authors: Z
authors: Han
authors: Yuanyuan
authors: Y
authors: Zhang
authors: Liying
authors: L
authors: Li
mesh_terms: D000328:Adult; D000368:Aged; D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000098:blood supply; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D042683:Angiopoietin-1; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C467630:ANGPT1 protein, human; C467628:Angpt1 protein, mouse; C060506:sphingosine 1-phosphate