Vascular endothelial growth/permeability factor (VEG/PF) has an established role in angiogenesis, however, the regulation of placental VEG/PF expression during primate pregnancy is incompletely understood. A temporal study was conducted in baboons to determine the effect of acute administration of estradiol on the expression of VEG/PF by cells of the villous placenta. VEG/PF mRNA levels were determined by reverse transcription-polymerase chain reaction in isolated placental cell fractions of baboons after acute i.v. and i.m. administration of estradiol. Within 2 h of estradiol treatment, VEG/PF mRNA (attomoles/ micrograms total RNA) increased within villous cytotrophoblasts to a level (mean ± SEM, 12 612 ± 2419) that was almost 2-fold greater (P < 0.05) than in untreated controls (6810 ± 1368). Cytotrophoblast VEG/PF mRNA levels remained elevated (P < 0.01) 6 h after estradiol treatment (15 006 ± 506), but were not different from controls 18 h after estradiol administration. VEG/ PF mRNA levels in whole villous tissue also were greater 6 h (12 667 ± 2284, P < 0.05) and 18 h (16 080 ± 3816, P < 0.01) after estradiol treatment than in untreated animals (3380 ± 594). In contrast, VEG/PF mRNA levels in cells of the inner villous core were not altered by estradiol treatment. Expression of both the VEG/PF₁₂₁ and VEG/PF₁₆₅ mRNA species appeared to increase in the placenta 6 h after estradiol treatment of baboons. We propose that estrogen regulates VEG/PF expression within the placenta in a cell-specific manner, providing a paracrine system to promote vascularization of the villous placenta during the first half of primate pregnancy.