Placental angiogenesis and growth are crucial elements in embryonic and later fetal development. Vascular endothelial growth factor (VEGF) and its specific receptors Flt-1 (VEGFR-1) and KDR (VEGFR-2) compose potent ligand receptor systems involved in angiogenesis and microvascular hyperpermeability. In the present immunohistochemical study, VEGF, Flt-1 and KDR were localized in uterus of cyclic non-pregnant pigs and in the porcine epitheliochorial placenta throughout gestation. Emphasis was placed on early gestational stages, where morphological studies have demonstrated extensive angiogenesis during initial placentation. The results revealed a high correlation in spatiotemporal distribution between the ligand and its receptors and a surprising demonstration of VEGF receptors in several non-endothelial cells. In non-pregnant pigs, VEGF, Flt-1 and KDR exhibited moderate to intense staining in uterine luminal epithelium and smooth muscle cells of the vessel walls. Endothelial cells of arteries and arterioles revealed labelling for Flt-1 and KDR, whereas the uterine glandular epithelium displayed intense KDR immunoreactivity at the late luteal phase. During gestation the uterine luminal epithelium demonstrated weak ligand and receptor immunostaining in the first half of early gestation [< or = 21 days post coitus (p.c.)], whereas later stages (> or = 21 days p.c.) displayed intense immunolabelling. Endothelial cells, smooth muscle cells of the vessel walls and uterine glandular epithelium revealed intense ligand and receptor immunoreactivity throughout gestation. In the fetal part of the placenta, VEGF, Flt-1 and KDR immunostaining displayed moderate to intense reactivity in the trophoblast throughout gestation, except during the second half of early gestation (days 21-30 p.c.). Fetal vessel walls were also immunopositive for VEGF, Flt-1 and KDR. Taken together, the results imply that the VEGF, Flt-1 and KDR ligand receptor system participate in the regulations of porcine placentation and that it in addition to its angiogenic properties also may influence the cellular differentiation and transport capabilities in uterine luminal as well as glandular epithelium and the trophoblast.