We discovered that oxygen tension, which has profound effects on blood vessels, controls the switch between cytotrophoblast proliferation and differentiation/invasion [6, 7]. In these experiments, control anchoring villus explants (6 to 8 weeks of gestation) were maintained in either a 20 percent or an 8 percent O2 atmosphere, mimicking standard culture conditions and the environment within the uterine interstitium, respectively. Other villi were cultured in 2 percent O2, mimicking the hypoxic conditions in the fetal compartment near the uterine lumen at this time. In 20 percent and 8 percent O2, CTBs exit the cell cycle, upreg-ulate integrin aipi, and become highly invasive. In hypoxia, CTBs continue to proliferate, but they fail to express aipi integrin and do not invade. These observations suggest the following model. Before CTBs access the maternal blood supply (e.g., at 10 weeks of gestation), the hypoxic environment near the uterine lumen in which early placental development occurs favors CTB proliferation, a phenomenon observed in situ. As interstitial invasion proceeds, invasive CTBs encounter a positive oxygen gradient that favors differentiation/invasion. The effects we observed are due, in part, to the actions of the von Hippel-Lindau tumor suppressor protein (pVHL), which regulates the stability of hypoxia-inducible factor-1a (HIFla and HIF2a and thus is pivotal in cellular responses to changes in oxygen tension. The results of in vitro experiments to study VHL function in CTBs, together with the placental defects previously observed in VHL~l~ mice, suggest that pVHL is a component of the mechanism that transduces local differences in oxygen tension at the maternal-fetal interface to changes in the biological behavior of CTBs .
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.