Fig. 1. Placental cytotrophoblasts invade the uterine wall where they breach veins and extensively remodel maternal spiral arterioles. The bulk of the placenta is composed of numerous tree-like projections termed chorionic villi where maternal-fetal exchange occurs. These structures mediate the passage of nutrients, gases and wastes between fetal blood, which circulates through the villous core, and maternal blood, which circulates through the intervillous space. The uteroplacental circulation is established by cytotrophoblasts that acquire an invasive/endothelial phenotype as they leave the placenta and enter the uterine wall. Differentiation begins when cytotrophoblast progenitors that reside in a single layer surrounding the stromal core of anchoring villi proliferate and form a cell column. These structures attach to the uterine wall and give rise to cells that invade the underlying decidual stroma. Invasive cytotrophoblasts breach uterine blood vessels connecting both the arterial and the venular circulation to the intervillous space. However, once this connection is made, remodeling of the venous side is halted. By contrast, cytotrophoblasts migrate up the lumina of spiral arterioles, eventually replacing the endothelial lining of the vessels and part of the muscular wall. This process encompasses the decidual and inner third of the myometrial segments of these vessels. NK, natural killer; m, macrophage.