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No treatment currently exists for pre-eclampsia, a gestational disorder which affects over 8 million pregnant women worldwide and can cause premature delivery or death of the mother or the fetus. In a study published in the journal Antioxidants & Redox Signaling, scientists from the CNRS, Inserm, the Institut Pasteur and INRA reveal that alterations in mitochondria located in the placenta and associated with the imbalance of reactive oxygen and nitrogen species could be the underlying cause of this condition. Their fundamental research opens up possibilities for developing new biomarkers for detecting pre-eclampsia in its early stages and exploring new therapeutic approaches.
Pre-eclampsia affects roughly 5% of all pregnancies and represents a major cause of morbidity and death among mothers, fetuses and newborns. This condition is responsible for 500,000 deaths each year, primarily in developing countries. In industrialized countries, pre-eclampsia is still a potentially serious complication of pregnancy. Warning signs include hypertension, proteinuria, edema (swelling) accompanied by severe headache, abdominal pain, blurred vision, vomiting, and confusion. In cases of pre-eclampsia where the mother's life is at risk, delivery by C-section is necessary. This is often carried out as an emergency procedure, well before the end of the normal gestation period, with potentially dramatic consequences for the infant. While symptomatic treatment is available to manage hypertension, no effective treatment for pre-eclampsia currently exists. Genetic studies carried out on at-risk human populations, which led to the development of pre-eclampsia models in mice, made it possible to focus research on the role played by a new transcription factor, STOX1, in the onset of this pathological condition.
Using these models, scientists showed that mitochondrial activity and the nitroso-redox balance (the ratio between reactive species of oxygen and nitrogen) are altered in placenta cells of pre-eclamptic mice and that this is directly linked to the elevated expression of STOX1. The nitroso-redox balance controls the equilibrium between oxidative and nitrosative stress which generates high levels of toxic molecules such as superoxide and peroxynitrite, both of which are normal products of cellular metabolism at lower concentrations. The role played by STOX1 in the regulation of oxidative/nitrosative stress is strongly influenced by oxygen pressure. This pressure varies naturally during pregnancy and is linked to mitochondrial homeostasis and nitric oxide (NO) metabolism. Nitric oxide is essential for vasodilation (the widening of blood vessels) and blood pressure regulation. When pre-eclampsia is induced by the over expression of STOX1, the nitroso-redox balance in the placenta is disrupted, resulting in a deficit of NO for the mother and impairing the response to physiological changes in oxygen pressure. This novel mechanism could explain the characteristic symptoms brought on by pre-eclampsia, in particular hypertension, proteinuria and increased oxidative stress.
This research opens up the possibility of characterizing new molecular markers for early-stage pre-eclampsia and developing therapeutic strategies that target the nitroso-redox balance, mitochondria, and nitric oxide metabolism.
Figure : 3D reconstructed sections of a placenta from a normal pregnant mouse (A-B) and a placenta from a pre-eclamptic pregnant mouse (C-D) observed using high-resolution confocal microscopy with immunofluorescence markings. Blue: nucleus; Green: mitochondria; Red: actin cytoskeleton. A and C: maternal cells; B and D: junctional zone. The green mitochondrial markings are more intense in the placenta of the pre-eclamptic mouse that those in the placenta of the non pre-eclamptic mouse.
© Laurent Chatre/Institut pasteur/CNRS
Nitroso-Redox Balance and Mitochondrial Homeostasis Are Regulated by STOX1, a Pre-Eclampsia-Associated Gene, Ludivine Doridot, Laurent Châtre, Aurélien Ducat, Jean-Luc Vilotte, Anne Lombès, Céline Méhats, Sandrine Barbaux, Rosamaria Calicchio, Miria Ricchetti, Daniel Vaiman, Antioxidants & Redox Signaling (2014), doi : 10.1089/ars.2013.5661