Developmental regulation of placental angiogenesis by estrogen during baboon pregnancy

Abstract

This study was designed to test the hypothesis that estrogen promotes neovascularization of placental villi during primate pregnancy by regulating developmental expression of the angiogenic factor vascular endothelial growth/permeability factor (VEG/PF). VEG/PF mRNA levels were determined in placental cell fractions by competitive RT-PCR and placental vascularity was quantified by image analysis in the baboon. A developmental study was conducted to determine the placental cell source and potential regulation of VEG/PF throughout gestation. Cytotrophoblasts were a major source of VEG/PF mRNA and protein in the baboon placenta and there was a developmental increase in cytotrophoblast VEG/PF mRNA expression and placental vascularization with advancing pregnancy in association with the rise in estrogen. To determine the role of exogenous estrogen, placental VEG/PF mRNA expression and angiogenesis were determined after acute or chronic estrogen treatment of baboons early in pregnancy (i.e. day 60, term = 184 days). Placental cytotrophoblast VEG/PF mRNA levels were upregulated (P < 0.05) within 2 h of acute estradiol treatment. Daily treatment of baboons with aromatizable androstenedione on days 30--59 of gestation elevated (P < 0.01) maternal serum estradiol levels and upregulated (P < 0.01) placental cytotrophoblast VEG/PF mRNA levels and placental vascularization. To determine the role of endogenous estrogen on angiogenesis in the first and second half of pregnancy, estrogen production in pregnant baboons was experimentally suppressed by administration of aromatase inhibitor CGS 20267 on days 25--59 or 25--169 of gestation, respectively. CGS administration resulted in a 95% decrease in estrogen levels and a four-fold decline (P < 0.05) in cytotrophoblast VEG/PF mRNA levels during early pregnancy, an effect reversed by concomitant administration of CGS 20267 plus estradiol. CGS 20267 administration had no effect on cytotrophoblast VEG/PF expression in the second half of gestation. Placental vascular parameters in all CGS 20267-treated baboons did not vary from controls. Collectively, these results are consistent with the hypothesis that estrogen has an important role in neovascularization of the developing villous placenta during early primate pregnancy and that VEG/PF mediates this process. In the second half of gestation, trophoblasts appear to lose their responsivity to estrogen and other factors may become important in regulating placental vascularization.