Preeclampsia is a condition that affects the placenta during pregnancy and is dangerous for both the fetus and the mother. Scientists from the Institut Pasteur, Inserm and CNRS have proposed a new therapy, tested on two rodent models, which corrects defects identified in placental cells and restores placental and fetal weight. The treatment successfully lowers blood pressure in the mother and resolves the characteristic preeclampsia symptoms of excess protein in the urine and cardiovascular abnormalities. The research was published July 30 in the journal Redox biology.
Preeclampsia is a placental dysfunction that affects approximately 2-8% of pregnant women worldwide. It can have life-threatening complications, with more than 50,000 maternal deaths each year and indirectly more than one million fetal or perinatal deaths worldwide. The main symptoms of preeclampsia are high blood pressure, proteinuria (increased protein levels in the urine), abnormal clotting of the placenta, cardiovascular abnormalities in the mother, and fetal growth retardation. Preeclampsia can also have long-term effects on the mother’s cardiovascular system, brain, liver, and kidneys many years after pregnancy. Current first-line treatment for preeclampsia is limited and involves the preventive use of aspirin in patients at risk. This treatment reduces the procoagulant state of the placenta and partly relieves the pressure on the vascular network.
Preeclampsia is characterized by a defective placenta caused by dysfunction of the trophoblast. Trophoblasts are specific cells of the placenta that help organize and manage the vascular network, allowing the supply of oxygen, nutrients and other essential elements for the growth of the fetus. At the molecular level, preeclampsia is characterized by an uncontrolled increase in oxidative stress, with excessive production of various reactive species, including reactive oxygen and nitrogen species. There is a genetic component: the first gene identified as being involved in the genetic forms of preeclampsia is the transcription factor STOX1, which controls the expression of thousands of genes, in particular those involved in the production of nitric oxide (NO ).
In a transgenic mouse model, a strong accumulation of STOX1 in the placenta induces a preeclampsia-like syndrome. In preeclampsia, nitric oxide, a powerful vasodilator that dilates blood vessels to promote blood flow to the placenta, is mobilized to produce potentially toxic molecules (nitrosative stress) and its levels become insufficient in the placental vascular network, affecting trophoblast function and the vascular network and destabilizing other reactive species. This creates a vicious circle and causes uncontrollable oxidative/nitrosative stress with multiple complications, also affecting the cells of the maternal blood vessels, with life-threatening consequences.
NO is produced by a family of enzymes known as nitric oxide synthases (NOS). Finding a way to restore NO production in the placenta via NOS could represent an effective new therapy to treat preeclampsia. A multi-year collaboration between the team led by Dr Daniel Vaiman (Institut Cochin, Inserm/CNRS/Université Paris Cité) and the team led by Dr Miria Ricchetti (Department of Developmental Biology and Stem Cells, Institut Pasteur /CNRS) with Dr Laurent Châtre, and more recently an American team from Mississippi, has surfaced a potential solution. The scientists’ research was based on trophoblasts overexpressing STOX1 and two models of preeclampsia in rodents, one mimicking early forms via placental overexpression of STOX1 and the other mimicking late forms via partial occlusion of the abdominal aorta. low.
The research revealed a cascade of events that ultimately led scientists to come up with a new therapy. Treatment of trophoblasts with BH4 (or tetrahydrobiopterin, a cofactor that stabilizes the NO-producing enzyme NOS) corrected the defects identified in these cells, restoring the production of NO rather than potentially toxic molecules. More importantly, administration of BH4 to both preclinical rodent models restored placental and fetal weight. Finally, in the early-onset STOX1 preclinical model with significant arterial hypertension and proteinuria, BH4 treatment corrected blood pressure, excess urine protein, and cardiovascular abnormalities in the mother. The results even suggest that the treatment may be effective in treating the long-term effects of preeclampsia on mothers (vascular abnormalities in the brain, kidneys, heart and liver).
This research is the first step towards developing a therapy for preeclampsia. The scientists also carried out genetic (transcriptomic) analyzes of placentas treated with BH4 and showed that it corrects the expression of several genes disrupted by the excess of STOX1 in a different way from the dysregulation induced by aspirin in the placenta. In conclusion, the scientists propose that a treatment combining BH4 and aspirin could be the ultimate therapeutic solution for many cases of preeclampsia. This hypothesis needs to be validated in clinical trials.
Chatre, L. et al. (2022) Increasing NOS coupling by the metabolite tetrahydrobiopterin (BH4) reduces the consequences of preeclampsia/IUGR. Redox biology. doi.org/10.1016/j.redox.2022.102406.