A potential target for treating preeclampsia

Twenty years ago, doctors and scientists thought that preeclampsia was a kind of hypertension. Today, doctors treat preeclampsia as a syndrome that affects the whole body. It causes inflammation, kidney and liver damage, low birth weight, and lifelong cardiovascular damage to both parent and child. Preeclampsia is one of the leading causes of maternal and fetal mortality worldwide, with more than 50,000 maternal deaths per year (1).

Despite its prevalence, no good treatments exist. Some pregnant people take aspirin prophylactically to reduce their preeclampsia risks, but the most commonly recommended treatment for the condition is to give birth. 

In the 2000s and 2010s, some medical researchers began investigating how problems with metabolism lead to preeclampsia. Other researchers identified a potential genetic component: a mutation in a gene called Storkhead box 1 (STOX1) that regulates metabolism in the placenta (2). A group of researchers recently connected the STOX1 gene to a treatable metabolic defect (3). In their study, they showed in mice that they could short circuit an overactive STOX1 genetic pathway that causes preeclampsia symptoms with a simple antioxidant. 

“From a scientific point of view, preeclampsia is very interesting because just 20 years ago, it was considered a disease of old mysteries,” said Daniel Vaiman, a reproductive biologist at the Cochin Institute and author of the study. 

In the 5th century BCE, Hippocrates postulated that the cause of preeclampsia was a dried up uterus wandering around the body looking for moisture. As of 2010, the actual cause of the disorder was still unknown (4). In 2011, Vaiman contacted Laurent Chatre, a biochemist then at the Pasteur Institute who specializes in metabolism and proposed a collaboration to help connect preeclampsia genetics and metabolism. This new paper published in Redox Biology is the third from their decade of working together.

The team noticed that placental cells with overexpressed STOX1 produced excess nitrogen oxide synthase (NOS) protein. NOS produces nitrogen oxide (NO), a signaling molecule that dilates blood vessels. Excess NOS increases oxidative stress and hypertension, a hallmark symptom of preeclampsia (5). Vaiman and Chatre reasoned that if increased STOX1 creates too much NOS, they could turn off NOS and see if that reduced hypertension. 

When bound to a cofactor called tetrahydrobipterin (often simply called BH4), NOS doesn’t produce as much oxidative stress. Preeclampsia patients have reduced BH4 in the body (6). To test their hypothesis, Vaiman and Chatre began putting BH4 in the drinking water of pregnant mice with preeclampsia. Adding BH4 to the diet corrected metabolic dysfunction created by increased amounts of STOX1 and NOS. Treatment with BH4 reduced hypertension and eliminated protein in the urine of pregnant mice with preeclampsia. In this way, BH4 acts as an antioxidant, counteracting oxidative stress.

During preeclampsia, the placenta releases excess free radicals such as superoxide (O₂^-), hydrogen peroxide (H₂O₂), and hydroxyl radicals (OH^-), also known as reactive oxygen species (ROS). The body produces and carefully regulates ROS through normal metabolic processes. When ROS levels are normal, ROS act as signaling molecules. When in excess, they are chemically reactive and produce oxidative stress. In this state, they can damage DNA, proteins, and cells.

Whether treating preeclampsia in mice by targeting oxidative stress will translate to humans is still not clear. “Unfortunately, humans are the only ones with their specific type of placenta,” said Kathryn Gray, an obstetrician and medical researcher at Brigham and Women’s Hospital who studies preeclampsia and was not involved in the study. Humans have a hemochorial placenta, where the mother’s blood is in direct contact with the placenta, an arrangement that no other species precisely mimics.

Because preeclampsia isn’t one disease but a syndrome that affects the whole body in multiple ways, there are multiple pathways to develop it. “We have to understand what the underlying etiology is. That might not be the same for every patient,” said Gray. “We might have an antioxidant therapy that is good for patients whose primary route to getting [preeclampsia] is too much oxidative stress in the placenta. But there're other patients who might have immune pathology.”

References

1. Duley, L. The Global Impact of Pre-eclampsia and Eclampsia. Seminars in Perinatology  33, 130–137 (2009).
2. Doridot, L. et al. Nitroso-Redox Balance and Mitochondrial Homeostasis Are Regulated by STOX1 , a Pre-Eclampsia-Associated Gene. Antioxidants & Redox Signaling  21, 819–834 (2014).
3. Chatre, L. et al. Increased NOS coupling by the metabolite tetrahydrobiopterin (BH4) reduces preeclampsia/IUGR consequences. Redox Biology  55, 102406 (2022).
4. Bell, M. J. A Historical Overview of Preeclampsia?Eclampsia. Journal of Obstetric, Gynecologic & Neonatal Nursing  39, 510–518 (2010).
5. Zimmet, J. M. & Hare, J. M. Nitroso–Redox Interactions in the Cardiovascular System. Circulation  114, 1531–1544 (2006).
6. Chuaiphichai, S. et al. Endothelial GTPCH (GTP Cyclohydrolase 1) and Tetrahydrobiopterin Regulate Gestational Blood Pressure, Uteroplacental Remodeling, and Fetal Growth. Hypertension  78, 1871–1884 (2021).