Cytotrophoblasts are specialized epithelial cells of the human placenta that differentiate to acquire tumor-like properties that allow them to invade the uterus. Concurrently, they develop endothelial-like characteristics. This transformation allows cytotrophoblasts to replace the maternal cells that line uterine vessels, thereby diverting maternal blood to the placenta. Previously, we showed that invading cytotrophoblasts secrete VEGF-C and PlGF, factors that regulate their acquisition of an endothelial-like phenotype. Here, we examined the cells' expression of angiopoietin ligands and their Tie receptors. The data show that cytotrophoblasts predominantly expressed Ang2. We also studied the paracrine functions of Ang2 and the VEGFs by culturing uterine microvascular endothelial cells in cytotrophoblast-conditioned medium, which supported their growth. Removal of VEGF-C, PlGF, and/or Ang2 from the medium caused a marked reduction in cell number due to massive apoptosis. We also assayed the angiogenic potential of cytotrophoblast-derived factors in the chick chorioallantoic membrane assay. The results showed that they stimulated angiogenesis to a level comparable to that of basic FGF. These data suggest that invasive human cytotrophoblasts use an unusual repertoire of factors to influence the angiogenic state of maternal blood vessels and that this cross talk plays an important part in the endovascular component of uterine invasion.