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

The endothelial cell-derived endothelin-1 (ET-1) is a potent mitogen for en dothelial cells, vascular smooth muscle cells, and tumor cells. In this stu dy, 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. T he ETB receptor (ETBR) antagonist, BQ 788, blocked the angiogenic effects i nduced by ET-1, whereas the ETAR antagonist was less effective. ET-1 stimul ated matt ix metalloproteinase-2 mRNA expression and metalloproteinase-2 pr oduction, as determined by reverse transcriptase-polymerase chain reaction and gelatin zymography, Furthermore ET-1 was able to enhance HUVEC differen tiation into cord vascular-like structures on Matrigel, When tested in comb ination 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 combinati on with VEGF stimulated an angiogenic response comparable to that elicited by basic fibroblast growth factor, These findings demonstrated that ET-1 in duces angiogenic responses in cultured endothelial cells through ETBR acid that stimulates neovascularization in vivo In concert with VEGF. ET-1 and i ts receptors acting as angiogenic regulators might represent new targets fo r anti-angiogenic therapy.