Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGF beta(3)

During early pregnancy, placentation occurs in a relatively hypoxic environ ment that is essential for appropriate embryonic development. Intervillous blood flow increases around 10 to 12 weeks of gestation and results in expo sure of trophoblast cells to increased oxygen tension. Before this time, lo w oxygen appears to prevent trophoblast differentiation toward an invasive phenotype. Using human villous explants of 5-8 weeks' gestation, we found t hat low oxygen tension triggered trophoblast proliferation, fibronectin syn thesis, alpha(5) integrin expression, and gelatinase A activity. These bioc hemical markers were barely detectable under oxic conditions. We therefore examined the placental expression of hypoxia-inducible factor-1 (HIF-1), a master regulator of oxygen homeostasis, and determined that expression of H IF-1 alpha subunit during the first trimester of gestation parallels that o f TGF beta(3), an inhibitor of extravillous trophoblast differentiation. Ex pression of both molecules is high in early pregnancy and falls around 9 we eks of gestation, when placental pO(2) levels are believed to increase. Inc reasing oxygen tension induced a similar decrease in expression in cultured explants. Moreover, antisense inhibition of HIF-1 alpha expression in hypo xic explants inhibited expression of TGF beta(3), arrested cell proliferati on, decreased alpha(5) expression and gelatinase A activity, and triggered biochemical markers of an invasive trophoblast phenotype such as alpha(1) i ntegrin and gelatinase B expression. These data suggest that the oxygen-reg ulated early events of trophoblast differentiation are in part mediated by TGF beta(3) through HIF-1 transcription factors.