Reduced FOXM1 expression limits trophoblast migration and angiogenesis and is associated with preeclampsia

Trophoblast cells are often compared to highly invasive carcinoma cells due to their capacity to proliferate in hypoxic conditions, and to exhibit analogous vascular, proliferative, migratory and invasive capacities. Thus, genes that are important for tumorigenesis, such as FOXM1 may also be involved in processes of trophoblast invasion. Indeed, we found Foxm1 protein and mRNA levels decreased as gestational age increased in rat’s placentae. Accordingly, when mimicking early placental events in vitro, protein and mRNA expression of FOXM1 increased from 21% to 8% O2, reaching its higher expression at 3% oxygen tension and dropping to very low levels at 1%O2. Remarkably, FOXM1 silencing was able to significantly decrease wound density by 27.9%, in comparison with those cells transfected with control siRNA. Moreover, tube formation assays showed that in the presence of conditioned media from siFOXM1-JEG-3 (3%O2), HUVEC cells were unable to efficiently form tubes, however, when onditioned media of JEG-3 cells overexpressing FOXM1 at 1%O2 was added, the ability of HUVEC to form tubule networks was restored. Additionally, qRT-PCR assays of FOXM1 knockdown and overexpression experiments in JEG-3 cells revealed that the depletion of FOXM1 at 3%O2 and overexpression of FOXM1 at 1%O2 led to downregulation and upregulation of VEGF transcriptional levels, respectively. Conversely, we also observed deregulation of FOXM1 in placentae derived from pregnancies complicated by preeclampsia. Therefore, we demonstrate that FOXM1 may be a new regulatory protein of early placentation processes, and that under chronic hypoxic conditions (1%O2) and in patients with PE, its levels decrease