Scientists at the March of Dimes Prematurity Research Center (PRC) at the University of California, San Francisco (UCSF) have illuminated a list of genes associated with cellular changes in the uterus during preeclampsia, shedding new light on the mysterious hypertensive disease of pregnancy.
The findings, published recently in npj Women’s Health, widen the aperture of preeclampsia research past the placenta, long understood by scientists as the key organ involved in the development of preeclampsia due to a shallow, or weak, placental implantation into the uterus.
From there, the disease causes a variety of abnormal biological events and in severe cases culminates in organ damage, seizures, stroke, or death. It is the second leading cause of maternal mortality globally and a major driver of preterm birth.
The addition of the uterine environment to the scientific spotlight on preeclampsia opens the door to the identification of novel biomarkers to screen pregnancies at risk and the development of therapeutics to stop the progression of the disease.
Using transcriptomic (genetic) data from four existing studies containing over 16,000 genes from 86 women with early onset preeclampsia, the PRC analysis identified a group of uterine genes relevant to preeclampsia, including four genes never before linked to the condition: MUC1, SDC4, NR2F1, and BMP5.
The paper also revealed novel links between preeclampsia and the extracellular matrix, a network of supportive proteins and fibers that surrounds uterine cells and regulates normal cell function.
“On the whole, this study expands how we think about preeclampsia and focuses on not just the placenta but also highlights the surrounding decidua and extracellular supporting tissues around the placenta that may be just as important as the placenta itself in the disease,” said study first author and UCSF PRC investigator Dr. Ophelia Yin, who is also a high risk obstetrician and assistant professor in maternal fetal medicine at UCSF.
In addition to finding uterine genes never before linked with preeclampsia, Dr. Yin and team saw associations between the disease and placental genes that have previously been tied to it, building the case that they are truly involved in preeclampsia and not just error associations. Those genes were ANKRD37 and SERPINA3.
The insights come from a unique study design that sought to learn more about the development of preeclampsia through a comparison between the disease and another placental disorder called placenta accreta. While this latter condition differs from preeclampsia in that it is much rarer than preeclampsia, is not a hypertensive disorder, and presents a danger to pregnant women due to a high risk of bleeding before and during delivery, it has two key similarities with preeclampsia that make it an ideal research partner for the disease. First, the condition also leads to high rates of preterm birth, and second, its origins are also in placental attachment. But instead of a shallow attachment as with preeclampsia, placenta accreta is characterized by a deep placental attachment.
“Since the conditions originate from opposing placental-uterine attachment relationships, we thought placenta accreta would help us learn about preeclampsia,” said Dr. Yin. “And it did — we saw inverse genetic expression between the two conditions.”
“For many relevant genes we identified, we saw upregulation in one condition and down regulation in the other, or vice versa.”
The placenta accreta data was vital to making associations about preeclampsia and the uterine environment. Although the preeclampsia dataset Dr. Yin studied had information on the gene expression of a myriad of cells involved in pregnancy, it did not include single cell data that would allow Dr. Yin to match interesting genes with the cells they send instructions to.
“That’s where the placenta accreta datasets came in,” said Dr. Yin. “They did contain single cell data, and the same genes we had narrowed in on for preeclampsia were showing up in uterine cells in placenta accreta.”
“So based on the placenta accreta data in our analysis and other single cell preeclampsia studies, we do think this [the uterine environment] is where the signal is coming from — and we will elucidate more from future single cell work.”
Dr. Yin said that down the line, the work could result in a biomarker for poor placental attachment that could identify women at risk of early onset preeclampsia, allowing doctors to intervene early and help patients avoid the worst outcomes. In addition, the research could lead to therapies that could strengthen placental attachment in women at risk.
“Theoretically, that therapy could be applied between pregnancies or after pregnancy to allow for a healthier uterine environment and prevent future preeclampsia,” she said. “There are many possibilities.”