Sphingosine-1-phosphate markedly induces matrix metalloproteinase and integrin-dependent human endothelial cell invasion and lumen formation in three-dimensional collagen and fibrin matrices

Biochem Biophys Res Commun. 2003 Dec 26;312(4):903-13. doi: 10.1016/j.bbrc.2003.11.017.


Endothelial cell invasion is a key step in angiogenic blood vessel formation. Sphingosine-1-phosphate (S1P) has been previously reported to play a role in endothelial cell proliferation, survival, migration, and angiogenesis. Here, we examine the ability of S1P to regulate human endothelial cell invasion into three-dimensional collagen or fibrin matrices. We show that S1P potently stimulated human endothelial cell invasion, lumen formation, and branching morphogenesis in collagen, and fibrin matrices, (5- and 15-fold increases in invasion were observed, respectively). The S1P-induced invasion response was pertussis-toxin sensitive and completely dependent on integrins. Addition of integrin blocking reagents revealed that the alpha2beta1 integrin regulated invasion in collagen matrices, while a combination of alphavbeta3 and alpha5beta1 integrins regulated invasion in fibrin. Additionally, the S1P-induced invasion response was dependent on matrix metalloproteinases (MMPs). Tissue inhibitor of metalloproteinase-3 (TIMP-3) was the only physiologic inhibitor of metalloproteinases that completely inhibited the potent stimulation of invasion induced by S1P. In contrast, TIMP-1 had no blocking effect on invasion or morphogenesis, while TIMP-2 and TIMP-4 partially reduced invasion but completely blocked lumen formation events. Collectively, these data reveal a marked ability of S1P to induce metalloproteinase- and integrin-dependent human endothelial cell invasion and morphogenesis in both collagen and fibrin three-dimensional matrices, the two most physiologically relevant matrices for angiogenesis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cells, Cultured
  • Collagen / physiology*
  • Dose-Response Relationship, Drug
  • Endothelial Cells / cytology*
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology*
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / physiology*
  • Fibrin / physiology*
  • Humans
  • Integrins / metabolism*
  • Lysophospholipids*
  • Matrix Metalloproteinases / metabolism*
  • Morphogenesis / drug effects
  • Morphogenesis / physiology
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism*
  • Sphingosine / pharmacology
  • Umbilical Veins / cytology
  • Umbilical Veins / drug effects
  • Umbilical Veins / physiology


  • Integrins
  • Lysophospholipids
  • sphingosine 1-phosphate
  • Fibrin
  • Collagen
  • Matrix Metalloproteinases
  • Sphingosine