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

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 ETB receptor (ETBR) antagonist, BQ 788, blocked the angiogenic effects induced by ET-1, whereas the ETAR antagonist was less effective. ET-1 stimulated matt ix 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 ETBR acid 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.