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(American Journal of Pathology. 2000;157:1703-1711.)
© 2000 American Society for Investigative Pathology

Regular Articles

Endothelin-1 Induces an Angiogenic Phenotype in Cultured Endothelial Cells and Stimulates Neovascularization In Vivo

Debora Salani*, Giulia Taraboletti{dagger}, Laura Rosanò*, Valeriana Di Castro*, Patrizia Borsotti{dagger}, Raffaella Giavazzi{dagger} and Anna Bagnato*

From the Laboratory of Molecular Pathology and Ultrastructure,*
Regina Elena Cancer Institute, Rome; and the Laboratory of Biology and Treatment of Metastasis,{dagger}
Mario Negri Institute for Pharmacological Research, Bergamo, Italy

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 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 ETBR 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.




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