CONICET | Buscador de Institutos y Recursos Humanos

Preeclampsia is a complication of pregnancy, unique to human gestation. According to the WHO, preeclampsia complicates 10 million pregnancies annually, resulting in 76,000 maternal deaths and 500,000 fetal or newborn deaths worldwide. In Latin America, preeclampsia is the first cause of maternal death. Its clinical presentation is highly variable, and it is diagnosed by the sudden onset of hypertension after the 20th week of gestation, in a previously normotensive woman, combined with signs of damage to another organ system, including the brain. Although its etiology remains unclear, this syndrome is associated with placental insufficiency, resulting in increased syncytiotrophoblast stress. This cellular stress may affect the placental transport functions altering the expression of different proteins such as aquaporins (AQPs). Among AQPs, AQP4 is of particular interest because it may be the link between placental failure and brain edema in preeclampsia.AQP4 belongs to the aquaporin subfamily that is selectively permeable for water. AQP4 was described in chorionic villi in the early stages of gestation, and its expression decreases throughout pregnancy. Recently, we reported that AQP4 gene expression was upregulated by hypoxia through a mechanism mediated by the hypoxia-inducible factor-1α (HIF-1α). Unexpectedly, despite the increase in HIF-1α, AQP4 protein dramatically decreased in preeclamptic placentas. Although this decrease may be due to an increase in its degradation, many reports have found that the lysosomal and proteasomal proteolytic degradation pathways are impaired in these placentas.On the other hand, AQP4 is one of the most abundant proteins in the brain and is mainly located in the pericapillary astrocytic end-feet. It is well-established that the expression of AQP4 in astrocytes may contribute to blood-brain barrier (BBB) properties by maintaining brain water homeostasis. However, excessive AQP4 may promote edema formation. Brain edema is considered a leading cause of seizures in preeclamptic women. Interestingly, the expression of AQP4 in the brain increases during pregnancy, and its levels were found to be upregulated after eclamptic seizures. However, the mechanism that promotes AQP4 increase in the eclamptic brain is still unknown. Recently, extracellular vesicles (EVs) were found to be responsible for cell communication in many tissues. Emerging evidence shows that during pregnancy, EVs can modulate signals not only on neighboring trophoblast and endothelial cells but also on distant cells of other organs. EVs may also be taken up and integrated into the target cells. Thus, placental EVs may be the best candidates to communicate the placenta and the brain. Recently, we investigated the expression of AQP4 in placental EVs isolated from plasma from pregnant women and we found detectable levels of AQP4 protein. We also studied the expression of AQP4 in EVs isolated from placental explants cultured in the presence of 250 μM CoCl2, a hypoxia-mimicking agent that inhibits HIF-1α degradation and induces syncytiotrophoblast stress. We observed an increase in AQP4 protein expression in these vesicles after CoCl2 treatment. Although further studies are needed, it is possible that placental AQP4 proteins can be transported to the brain via EVs and may be taken up and function in the astrocytes. Thus, AQP4 may increase its expression in astrocytes during pregnancy, without producing edema under normal circumstances. In preeclampsia, the syncytiotrophoblast stress enhances EVs´ detachment into the maternal circulation, which likely also may increase the levels of AQP4 positive EV. Consequently, AQP4 expression in the preeclamptic brain may also increase. However, only in the presence of any stressor that can disturb the BBB, the increase in AQP4 may predispose to more edema production, leading to eclamptic seizures.

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