Human cytotrophoblast expression of the von Hippel-Lindau protein is downregulated during uterine invasion in situ and upregulated by hypoxia in vitro

The von Hippel-Lindau tumor-suppressor protein (pVHL) regulates the stabili ty of HIF1 alpha and HIF2 alpha and thus is pivotal in cellular responses t o changes in oxygen tension. Paradoxically, human cytotrophoblasts prolifer ate under hypoxic conditions comparable to those measured in the early gest ation placenta (2% O-2), but differentiate into tumorlike invasive cells un der well-oxygenated conditions such as those found in the uterus. We sought to explain this phenomenon in terms of pVHL expression. In situ, pVHL immu nolocalized to villous cytotrophoblast stem cells, and expression was enhan ced at sites of cell column initiation; in both of these relatively hypoxic locations, cytoplasmic staining for HIF2a was also detected. As cytotropho blasts attached to and invaded the uterus, which results in their increased exposure to oxygen, pVHL staining was abruptly downregulated concordant wi th localization of HIF2a to the nucleus. In vitro, hypoxia (2% O-2) upregul ated cytotrophoblast pVHL expression together with HIF2 alpha, which locali zed to the cytoplasm; culture under well-oxygenated conditions greatly redu ced levels of both molecules. These results, together with the placental de fects previously observed in VHL-/- 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 cytotrop hoblasts. Furthermore, these data provide the first example of oxygen-depen dent changes in pVHL abundance. (C) 2001 Academic Press.