OVER-EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR AND ITS RECEPTOR DURING THE DEVELOPMENT OF ESTROGEN-INDUCED RAT PITUITARY-TUMORS MAY MEDIATE ESTROGEN-INITIATED TUMOR ANGIOGENESIS

Estrogens, which have been associated with several types of human and animal cancers, can induce tumor angiogenesis in the pituitary of Fisc her 344 rats, The mechanistic details of tumor angiogenesis induction, during estrogen carcinogenesis, are still unknown. To elucidate the r ole of estrogen in the regulation of tumor angiogenesis in the pituita ry of female rats, the density of blood vessels was analysed using fac tor Vm related antigen (FVIIIRAg) immunohistochemistry and the express ion of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) was examined by Western blot and immunohistochemical analy sis, The expression of VEGF receptor (VEGFR-2/Flk-1/KDR) was also exam ined by immunohistochemistry, The results demonstrated that 17 beta-es tradiol (E2) induces neovascularization, as well as the growth and enl argement of blood vessels after 7 days of exposure. The high tumor ang iogenic potential was associated with an elevated VEGF/VPF protein exp ression in the E2 exposed pituitary of ovariectomized (OVEX) rats, VEG F/VPF and FVIIIRAg immunohistochemistry and endothelial specific lecti n (UEA1) binding studies, indicate that the elevation of VEGF protein expression initially occurred in both blood vessels and non-endothelia l cells, After 15 days of E2 exposure, VEGF/VPF protein expression, in the non-endothelial cell population, sharply declined and was restric ted to the blood vessels, The function of non-endothelial-derived VEGF is not clear, Furthermore, immunohistochemical studies demonstrated t hat VEGFR-2 (flk-1/KDR), expression was elevated significantly in the endothelial cells of microblood vessels after 7 days of E2 exposure, T hese findings suggest that over expression of VEGF and its receptor (V EGFR-2) may play an important role in the initial step of the regulati on of estrogen induced tumor angiogenesis in the rat pituitary.