Relación de la expresión del factor inducido por hipoxia-2α (HIF-2α) y sVEGF-R1/sFlt-1: implicación en la fisiopatología de preeclampsia

Trophoblast invasion is critical for the establishment of uteroplacental circulation. At the early phases of this process, local oxygen pressure in the placenta is lower, which pathologically remains constant in preeclampsia. Consequently, understanding the response of placental cells to these stimuli is important. In the present study, we used primary cultures of trophoblast cells (TCs), fibroblasts from villous cells, and human umbilical endothelial cells isolated from preterm and term placentas (with and without preeclampsia) to explore the effect of oxygen pressure on the expression and synthesis of VEGF, sVEGFR-1/sFlt-1, and HIF-1α and-2α. Our results show that low oxygen pressure led to a significant selective increase in mRNA and the sVEGF-R1 receptor protein in TCs. VEGF expression and synthesis was elevated in three cell types, but free protein (not bound to sVEGF-R1) was decreased in TCs. Expression of HIF-1α or -2α mRNA in cells was similar in all the types of placentas, but the increase in HIF-2α protein was greater in the TCs of preeclamptic placentas. To evaluate the relationship between HIF-2α and the increase in the sVEGFR-1 receptor, we used siRNAHIF2α. In response to inhibition, expression of the sVEGF-R1 receptor diminished dramatically. HIF-2α blockade did not alter VEGF expression. Our data are the first to indicate that the HIF-2α transcription factor protein is one of the molecules involved in the selective expression of the sVEGF-R1 receptor in TCs during hypoxia.