Differential expression of angiogenic and vasodilatory factors by invasive trophoblast giant cells depending on depth of invasion.
The uterine bed undergoes remarkable changes during pregnancy, including proliferation and decidualization of the uterine stroma and remodeling and angiogenesis of the maternal vasculature. Fetal-derived trophoblast giant cells invade into the uterus where they gain access to the maternal blood circulation to ensure sufficient nutrient supply of the embryo. In serial sections through early- to mid-gestation conceptuses, we have determined the exact distance of trophoblast invasion and the expression of angiogenic, vasodilatory, and anticoagulative factors that are likely to influence remodeling and redirection of the maternal circulatory system. Trophoblast derivatives were detected at a distance as far as approximately 300 microm from the placental border, where they are allocated exclusively along the mid-line of the decidua. The farthest invading cells characteristically expressed proliferin and proliferin-related protein, hormones that affect endothelial cell migration and vascularization. Occasionally, these cells replaced the normal vascular endothelium and acquired a "pseudo-endothelial" shape. Complete vascular disintegration was observed 50-80 microm outside of the placental border where maternal blood was entirely lined by a trophoblast giant cell-derived network of blood sinuses. This transition in blood space lining correlated with trophoblast expression of various vasodilatory and anticoagulative factors that are likely to promote blood flow toward the placenta. Analysis of teratocarcinoma-like tumors demonstrated that trophoblast giant cell-induced promotion and redirection of blood flow is not restricted to the uterine environment. These results show that trophoblast giant cells have the intrinsic capacity to attract and increase blood flow and to gradually displace the vascular endothelium resulting in the formation of canals entirely lined by trophoblast cells.