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 andanimal cancers, can induce tumor angiogenesis in the pituitary of Fischer344 rats. The mechanistic details of tumor angiogenesis induction, duringestrogen carcinogenesis, are still unknown. To elucidate the role ofestrogen in the regulation of tumor angiogenesis in the pituitary of femalerats, the density of blood vessels was analysed using factor VIII relatedantigen (FVIIIRAg) immunohistochemistry and the expression of vascularendothelial growth factor/vascular permeability factor (VEGF/VPF) wasexamined by Western blot and immunohistochemical analysis. The expressionof VEGF receptor (VEGFR-2/Flk-1/KDR) was also examined byimmunohistochemistry. The results demonstrated that 17beta-estradiol (E2)induces neovascularization, as well as the growth and enlargement of bloodvessels after 7 days of exposure. The high tumor angiogenic potential wasassociated with an elevated VEGF/VPF protein expression in the E2 exposedpituitary of ovariectomized (OVEX) rats. VEGF/VPF and FVIIIRAgimmunohistochemistry and endothelial specific lectin (UEA1) bindingstudies, indicate that the elevation of VEGF protein expression initiallyoccurred in both blood vessels and non-endothelial cells. After 15 days ofE2 exposure, VEGF/VPF protein expression, in the non- endothelial cellpopulation, sharply declined and was restricted to the blood vessels. Thefunction of non-endothelial-derived VEGF is not clear. Furthermore,immunohistochemical studies demonstrated that VEGFR- 2 (flk-1/KDR),expression was elevated significantly in the endothelial cells ofmicroblood vessels after 7 days of E2 exposure. These findings suggest thatover expression of VEGF and its receptor (VEGFR-2) may play an importantrole in the initial step of the regulation of estrogen induced tumorangiogenesis in the rat pituitary.