We have shown that advancing the increase in maternal serum estrogen levels from the second to the first third of baboon pregnancy suppressed extravillous cytotrophoblast (EVT) spiral artery invasion. Because vascular endothelial growth factor (VEGF) promotes EVT invasion, the present study determined whether EVT VEGF expression is altered by prematurely elevating estrogen in early pregnancy. Placental basal plate was obtained on d 60 of gestation (term is 184 d) from baboons treated daily on d 25-59 with estradiol (0.35 mg/d sc), which increased maternal peripheral serum estradiol levels 3-fold above normal. Overall percentage of uterine arteries (25 to more than 100 microm in diameter) invaded by EVT assessed by image analysis in untreated baboons (29.11+/-5.78%) was decreased 4.5-fold (P<0.001) by prematurely elevating estrogen (6.55+/-1.83%). VEGF mRNA levels in EVT isolated by laser capture microdissection from the anchoring villi of untreated baboons (6.77+/-2.20) were decreased approximately 5-fold (P<0.05, ANOVA) by estradiol (1.37+/-0.29). Uterine vein serum levels of the truncated soluble fms-like receptor, which controls VEGF bioavailability, in untreated baboons (403+/-37 pg/ml) were increased 3-fold (P<0.01) by estrogen treatment (1127+/-197 pg/ml). Thus, placental EVT expression of VEGF mRNA was decreased and serum soluble truncated fms-like receptor levels increased in baboons in which EVT invasion of the uterine spiral arteries was suppressed by advancing the rise in estrogen from the second to the first third of pregnancy. We suggest that VEGF mediates the decline in EVT vessel invasion induced by estrogen in early primate pregnancy.