The uterine response to 17beta-estradiol (E2) includes increased water retention, enhanced vascular permeability, DNA and RNA synthesis, and increased cellular mitosis. We have used the natural antagonist of vascular endothelial growth factor A (VEGF-A), sflt-1 (soluble form of flt-1), to determine whether the edematous and proliferative effects of E2 in the uterus are mediated by VEGF-A. Female BALB/c mice were ovariectomized and treated with E2 (10 micro g/kg) in the absence or presence of sflt-1 (0.8 and 4.0 mg/kg) for 24 h. E2 induced increases in uterine mass from 25.3 to 36.8 mg, in total cross-sectional uterine area from 771 to 1133 micro m(2), in cross-sectional endometrial area from 268 to 569 micro m(2), and in the mitotic index of lumenal epithelial cells from 0% to 53%. Antagonism with sflt-1 reduced the E2-induced increases in total uterine area to 779 micro m(2), endometrial area to 398 micro m(2) and the mitotic index of lumenal epithelial cells to 25%, but the E2-induced increase in uterine mass was not significantly reduced. From these data we conclude that the edematous response and proliferation of lumenal epithelial cells in the murine uterus are mediated in part through VEGF-A. These data suggest that sflt-1 could be a useful anti-VEGF-A agent and may be effective in modifying uterine biology.