Role of endothelin-1 in neovascularization of ovarian carcinoma

Endothelin-1 (ET-1) is overexpressed in ovarian carcinomas and acts, via ET A receptors (ETAR), as an autocrine growth factor. In this study we investi gate the role of ET-1 in the neovascularization of ovarian carcinoma. Archi val specimens of primary (n = 40) and metastatic (n = 8) ovarian tumors wer e examined by Immunohistochemistry for angiogenic factor and receptor expre ssion and for microvessel density using antibodies against CD31, ET-1, vasc ular endothelial growth factor (VEGF), and their receptors. ET-1 expression correlated with neovascularization and with VEGF expression. The localizat ion of functional ETAR and ETAR mRNA expression, as detected by autoradiogr aphy and irt situ hybridization, was evident in tumors and In intratumoral vessels, whereas ETBR were expressed mainly in endothelial cells. High leve ls of ET-1 were detected in the majority of ascitic fluids of patients with ovarian carcinoma and significantly correlated with VEGF ascitic concentra tion. Furthermore ET-1, through ETAR, stimulated VEGF production in an ovar ian carcinoma cell Line, OVCA 433, by an extent comparable to hypoxia. Fina lly, conditioned media from OVCA 433 as well as ascitic fluids caused an In crease in endothelial cell migration and the ET-1 receptor blockade signifi cantly inhibited this angiogenic response. These findings indicate that ET- 1 could modulate tumor angiogenesis, acting directly and in part through VE GF.