Vascular endothelial growth factor is an important vasodilator and effector of permeability in systemic blood vessels. Molecular and tissue culture techniques have provided evidence for its placental synthesis and release. Using an in vitro dual perfusion model of the term placental lobule from normal pregnancy, we report here the relative secretion of total VEGF, sVEGFR-1 and free VEGF into the maternal and fetoplacental circulations of the placenta. We tested the hypothesis that VEGF has vasomotor and permeability effects in the fetoplacental circulation of the human placenta and we examined the broad intracellular pathways involved in the vasodilatory effect which we found. We show that total VEGF is released into the fetal and maternal circulations in a bipolar fashion, with a bias towards maternal side output. Soluble VEGFR-1 was also secreted into both circulations with bias towards the maternal side. Consequently, free VEGF (12.8 +/- 2.4 pg / ml, mean +/- SE) was only found in the fetoplacental circulation. VEGF-165 was found to be a potent vasodilator of the fetoplacental circulation (maximum response: 77% of previous steady state fetal-side inflow hydrostatic pressure following preconstriction with U46619; EC50 = 71 pM). This vasodilatory effect was mediated by the VEGFR-2 receptor and nitric oxide in a manner independent of the involvement of prostacyclin and the src-family tyrosine kinases. However, nitric oxide could only explain 50% of the vasodilatory effect. Finally, we measured the permeability of the perfused placenta to inert hydrophilic tracers and found no difference in the presence and absence of VEGF.