New research suggests cellular stress in the placenta could be a possible cause of preeclampsia

Preeclampsia is a mysterious condition that occurs in about one in 10 pregnancies without any warning signs. After 20 weeks or more of normal blood pressure during pregnancy, patients with preeclampsia will begin to experience elevated blood pressure and may also experience increased protein levels in the urine due to hypertension reducing filtering power kidneys. Prolonged hypertension due to preeclampsia can lead to organ damage and life-threatening complications for the mother and fetus.

There is no cure for the underlying causes of preeclampsia, so doctors focus on managing and monitoring patients’ blood pressure to allow a gestation to be as close to full term as possible. In cases of serious illness, premature deliveries are necessary.

“For some patients who may reach term, a diagnosis of preeclampsia is scary at first, but ultimately it’s a bump in the road,” says Jennifer McIntosh, DO, MS, associate professor of obstetrics and medicine. gynecology at the Medical College of Wisconsin (MCW). ). “For those who catch it early, it can be terrifying and life-changing, potentially including a long hospital stay before delivery and significant supportive care for the infant in the NICU afterward.”

Additional research is needed into the causes of preeclampsia to guide the development of potential new ways to diagnose, treat, and prevent this common but enigmatic condition.

“The global incidence of preeclampsia is increasing, so research is becoming more important every day,” says Dr. McIntosh. “Preeclampsia has been around for as long as women have been giving birth, and yet the only cure is to give birth. I believe we can be innovative and do better for our patients.”

MCW scientists have published the results of a study investigating one of the emerging theories about the causes of preeclampsia in Scientists progress.

The experiments focus on a particular layer of cells in the placenta called the syncytiotrophoblast (STB), which forms a key part of the barrier between the mother and the developing fetus. This blockage helps prevent the mother’s fully formed immune system from responding to the fetus and potentially reacting as if the fetus were a foreign threat such as a viral or bacterial invader.

The barrier also works in reverse to prevent the fetus’ growing immune system from reacting to its mother’s cells and tissues. The study authors investigated the hypothesis that an abnormal amount of cellular and molecular stress on the STB can damage the placenta and lead to preeclampsia.

“There is ample evidence that these stresses accumulate, but how and why this happens remains an open question,” says Justin Grobe, Ph.D., MCW professor of physiology and biomedical engineering and co-corresponding author of the ‘study. Scientists progress manuscript with Dr. McIntosh. “We felt it was important to continue to validate the STB stress findings before moving forward with work on our hypothesis that elevated pregnancy hormones contribute to stress accumulation by overstimulating the STB.”

The research team began by studying placentas donated for research purposes through the MCW Maternal Research Placenta and Cord Blood Bank. By comparing “normal” placentas with placentas from pregnancies where patients had preeclampsia, researchers demonstrated that preeclampsia was associated with higher levels of cellular stress in the STB layer of the placenta. Additionally, the researchers discovered a hyperactive level of activity of the Gαq protein known to play a role in transmitting signals related to the levels of several hormones present in excessive amounts during preeclampsia.

“The donated human placenta samples were critical in identifying potential mechanisms of STB stress,” says Megan Opichka, Ph.D. ’23, research and development scientist at BioSpyder Technologies and first author of the publication. “As these samples are collected upon delivery, we then had to develop an animal model to determine whether these sources of stress could actually be the cause.”

Based on findings of overactive signaling via G protein-coupled receptors (GPCRs) in samples from patients with preeclampsia, scientists developed a new genetically engineered mouse model to enable the precise manipulation of GPCR signals within specific cell types. This allowed the researchers to activate signaling pathways associated with preeclampsia within the STB layer of the mouse placenta.

The team demonstrated that even very brief activation of the signaling cascades identified during early or mid-gestation led to significant consequences during mouse pregnancy. These mice developed all the characteristic signs of preeclampsia, including high blood pressure, kidney damage, and other anatomical and cellular changes.

In some mice exposed to preeclampsia-inducing signals, scientists tested the effects of a drug that reduces stress on the mitochondria that generate energy within each cell. The drug provided substantial protection against the development of signs and symptoms of preeclampsia.

“With our unique model, we can study the effects of factors contributing to preeclampsia throughout pregnancy,” says Dr. Grobe. “We can test specific signaling cascades in specific cells and tissues at specific times to observe their effects. We have only scratched the surface of what we can learn.”

“This will certainly be a springboard for future research,” adds Dr McIntosh. “As the drug we tested, MitoQ, is generally known to be safe, we are working on plans for a clinical pilot study to test appropriate dosing and effectiveness before pursuing larger clinical studies in preeclampsia at the future.”

So, can preeclampsia be prevented? Even if today the answer is no, MCW scientists have now taken a step further with these experimental results. And they continue to work as a team to achieve this goal through additional studies.

“What drives my research is my frustration with the lack of understanding of the causes of preeclampsia,” says Dr. McIntosh. “We need to continue to connect the bench and the bedside so we can understand the causes and use them to bring a cure to the bedside.”