Placental growth factor (PlGF) is produced mainly by the placenta and impairment of its signaling has been reported in preeclampsia. We tested the effect of PlGF on mesenteric veins (MV), and defined the underlying molecular mechanisms involved in its action. Third order MV isolated from pregnant rats were cannulated and pressurized (6 mmHg) in an arteriograph, and preconstricted 40-50% (with U46619) prior to being exposed to PlGF(1pM-3?M). In addition to endothelium-denuded vessels, reactivity was also assessed in intact MV in presence of NOS + COX inhibition. PlGF induced max vasodilation (59 ± 4.7%) of intact MV, and this effect was significantly abolished by endothelial denudation. In intact veins, the NOS inhibition but not COX inhibition, significantly reduced PlGF dilation. Also a significant reduction by potassium-depolarizing solution (30 mM) confirming its dependence on endothelial derived hyperpolarizing factor (EDHF). We tested the involvement of calcium-activated potassium channels (SK, IK) by pre-treating vessels with pharmacological inhibitors of channel subtypes. PlGF dilation was significantly inhibited by apamin and tram 34, implicating endothelial SK and IK channels in the underlying mechanism. In summary, PlGF vasodilation of MV is mainly mediated by endothelium-derived relaxation factors (NO and EDHF) and only in part by smooth muscle cells. The vasodilator effect of PlGF suggesting his important role in regulating gestational hemodynamic changes.