Regulation of vascular endothelial growth factor expression by estrogens and progestins

Estrogens increase the expression of vascular endothelial growth factor (VE GF) mRNA in the rodent uterus. This regulatory effect is rapid, beginning w ithin 1 hr after hormone treatment, dose dependent, and blocked by the pure antiestrogen ICI 182,780. The induction of the transcript is blocked by in hibitors of RNA but not of protein synthesis, and we have recently identifi ed estrogen response elements in the VEGF gene. Collectively, these finding s indicate that estrogens regulate uterine VEGF expression at the transcrip tional level via the classical nuclear estrogen receptor pathway. Estrogen induction of VEGF occurs in the stromal layer of the rodent uterus, and est radiol induces expression of VEGF transcript levels in cultured human uteri ne stromal cells. Progestins also induce VEGF expression in the rodent uter us, although the effect is less marked and slower in onset than estrogenic effects. The effect of progestins is blocked by the antiprogestin mifeprist one (RU-486), suggesting that it is also mediated by a classical nuclear re ceptor pathway. In addition, progestins regulate expression of VEGF mRNA an d protein in cultured human T47-D breast cancer cells. The development of u terine leiomyomas is associated with exposure to ovarian sex steroids, abno rmal uterine bleeding is commonly seen in patients with leiomyomas, and fib roids require an increased vascular supply for their growth. These observat ions suggest that VEGF and other angiogenic factors may represent potential targets for the treatment and prevention of uterine fibroids.