Preeclampsia may be linked to cellular stress in the placenta, study suggests

Preeclampsia, a condition that affects up to 10 per cent of pregnancies worldwide, could be linked to cellular stress in the placenta, new research has shown.

The study, conducted by researchers from the Medical College of Wisconsin (MCW) and published in the Science Advances journal, investigated the hypothesis that an abnormal amount of cellular and molecular stresses to a particular layer of cells of the placenta is associated with preeclampsia.

Preeclampsia is a condition that occurs in about one of 10 pregnancies. After 20 weeks or more of normal blood pressure during the pregnancy, patients with preeclampsia will begin to experience elevated blood pressure and may also have increased levels of protein in their urine due to hypertension reducing the filtering power of the kidneys.

Although many cases are mild, the condition can lead to serious complications for both mother and baby if it is not monitored and treated. Prolonged hypertension due to preeclampsia can lead to organ damage and life-threatening complications for mothers and foetuses.

“For some patients who can make it to full term, a preeclampsia diagnosis is scary at first but ultimately a bump in the road,” said Jennifer McIntosh, associate professor of obstetrics and gynaecology at the MCW.

“For those who get it earlier on, 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 afterwards.

“It is a condition that has existed for as long as women have been giving birth, and yet the only cure for it is delivering the baby.”

MCW scientists aimed to better understand the cause of preeclampsia by focusing on a particular layer of cells of the placenta called the syncytiotrophoblast (STB), a key part of the barrier between the mother and developing foetus.

The authors investigated the hypothesis that abnormal levels of cellular and molecular stresses to the STB can damage the placenta and lead to preeclampsia.

“There is considerable evidence that these stresses accumulate, however, how and why it happens continues to be an open question,” explained Justin Grobe, MCW professor of physiology and biomedical engineering.

“We felt it was important to continue to validate the STB stress findings before advancing work on our hypothesis that elevated hormones of pregnancy contribute to the accumulation of stress by overstimulating the STB.”

The research team studied placentas donated for research purposes. By comparing “normal” placentas with placentas from pregnancies where patients suffered from preeclampsia, investigators demonstrated that preeclampsia was associated with higher levels of cellular stresses in the STB layer on the placenta.

Additionally, the researchers found 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.

Megan Opichka, research and development scientist at BioSpyder Technologies and first author on the publication, said: “The donated human placenta samples were critical to identifying potential mechanisms of STB stress.

“Because these samples are collected upon delivery, we then needed to develop an animal model to determine if these sources of stress may actually be causative.”

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

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

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

“With our unique model, we can study the effects of contributing factors to preeclampsia throughout pregnancy,” Dr Grobe explained.

“We can test specific signalling cascades in specific cells and tissues at specific times to observe their effects. We have only scratched the surface on what we can learn.”

“Because the drug we tested is generally known to be safe, we’re working on plans for a clinical pilot study to test appropriate dosage and efficacy in advance of pursuing larger clinical studies of preeclampsia in the future,” added Dr McIntosh.

“What drives my research is my frustration about the lack of understanding of what causes preeclampsia. We need to continue linking the bench and the bedside together so that we can understand the causes and use them to bring a cure to the bedside.”