Hypoxia-inducible factor 2 alpha impairs human cytotrophoblast syncytialization: New insights into placental dysfunction and fetal growth restriction

Insufficient remodeling of uterine arteries causes pregnancy-related diseases, including fetal growth restriction and preeclampsia. In these situations, reduced maternal blood flow in the placenta is thought to be responsible for the persistence of a low oxygen environment throughout pregnancy. We hypothesized that chronic activation of transcription factors hypoxia-inducible factors (HIFs) actively participates in placental underdevelopment, which impairs fetal growth. The computer-assisted analysis in pathological placentas revealed an increased number of HIF-2 alpha-positive nuclei in the syncytium compared to normal human placentas, while HIF-1 alpha stabilization was unchanged. Specific involvement of HIF-2 alpha was confirmed in primary human cytotrophoblasts rendered deficient forHIF1AorHIF2A. SilencingHIF2Aincreased the expression of main syncytialization markers as well as differentiation and syncytium formation. It also improved placental growth factor bioavailability. None of these changes was seen when silencingHIF1A. Conversely, the experimental induction of HIF-2 alpha expression repressed forskolin-induced differentiation in BeWo choriocarcinoma cells. Our mechanistic insights evidence that transcription factor HIF-2 alpha impairs placental function, thus suggesting its participation in fetal growth restriction and preeclampsia when placentas become chronically hypoxic. Furthermore, it suggests the possibility to develop novel molecular targeting therapies for placental dysfunction.