Oxygen tension plays an important role in guiding the differentiation process that leads to cytotrophoblast invasion of the uterus. (A) The early stages of placental development take place in a relatively hypoxic environment that favors cytotrophoblast proliferation rather than differentiation along the invasive pathway. Accordingly, this cell population (light green cells) rapidly increases in number as compared with the embryonic lineages. (B) As development continues, cytotrophoblasts (dark green cells) invade the uterine wall and plug the maternal vessels, a process that helps maintain a state of physiological hypoxia. As indicated by the blunt arrows, cytotrophoblasts migrate farther up arteries than veins. (C) By 10 to 12 weeks of human pregnancy, blood flow to the intervillous space begins. As the endovascular component of cytotrophoblast invasion progresses, the cells migrate along the lumina of spiral arterioles, replacing the maternal endothelial lining. Cytotrophoblasts are also found in the smooth muscle walls of these vessels. In normal pregnancy the process whereby placental cells remodel uterine arterioles involves the decidual and inner third of the myometrial portions of these vessels. As a result, the diameter of the arterioles expands to accommodate the dramatic increase in blood flow that is needed to support rapid fetal growth later in pregnancy. It is likely that failed endovascular invasion leads, in some cases, to abortion, whereas an inability to invade to the appropriate depth is associated with preeclampsia and a subset of pregnancies in which the growth of the fetus is restricted.