Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo

Am J Pathol. 2000 Nov;157(5):1703-11. doi: 10.1016/S0002-9440(10)64807-9.


The endothelial cell-derived endothelin-1 (ET-1) is a potent mitogen for endothelial cells, vascular smooth muscle cells, and tumor cells. In this study, we analyzed the role of ET-1 on human umbilical vein endothelial cell (HUVEC) phenotype related to different stages of angiogenesis. ET-1 promoted HUVEC proliferation, migration, and invasion in a dose-dependent manner. The ET(B) receptor (ET(B)R) antagonist, BQ 788, blocked the angiogenic effects induced by ET-1, whereas the ET(A)R antagonist was less effective. ET-1 stimulated matrix metalloproteinase-2 mRNA expression and metalloproteinase-2 production, as determined by reverse transcriptase-polymerase chain reaction and gelatin zymography. Furthermore ET-1 was able to enhance HUVEC differentiation into cord vascular-like structures on Matrigel. When tested in combination with vascular endothelial growth factor (VEGF), ET-1 enhanced VEGF-induced angiogenic-related effects on endothelial cells in vitro. Finally, using the Matrigel plug neovascularization assay in vivo, ET-1 in combination with VEGF stimulated an angiogenic response comparable to that elicited by basic fibroblast growth factor. These findings demonstrated that ET-1 induces angiogenic responses in cultured endothelial cells through ET(B)R and that stimulates neovascularization in vivo in concert with VEGF. ET-1 and its receptors acting as angiogenic regulators might represent new targets for anti-angiogenic therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Cell Division / drug effects
  • Cell Movement / drug effects
  • Cells, Cultured
  • Drug Synergism
  • Endothelial Growth Factors / physiology
  • Endothelin-1 / pharmacology*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiology*
  • Humans
  • Lymphokines / physiology
  • Matrix Metalloproteinase 2 / metabolism
  • Neovascularization, Pathologic / etiology*
  • Neovascularization, Pathologic / genetics*
  • Phenotype
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Endothelial Growth Factors
  • Endothelin-1
  • Lymphokines
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Matrix Metalloproteinase 2