VGLL3 Gene Dysregulation Identified as Root Cause of Preeclampsia, Opening Door to New Diagnostics and Treatments
核心洞察
Researchers at the University of Michigan have identified dysregulation of the VGLL3 (搜索) gene in placental trophoblast cells as a potential root cause of preeclampsia (搜索), published in Circulation.
Overexpression of VGLL3 (搜索) caused high blood pressure in mouse models, while inhibition or deletion of the gene resulted in normal, healthy pregnancies.
The discovery emerged from a dermatology lab studying autoimmune disease sex differences, highlighting the value of cross-disciplinary collaboration.
A serendipitous discovery originating in a dermatology laboratory at the University of Michigan has illuminated what may be the root cause of preeclampsia (搜索), a serious pregnancy complication that has confounded researchers for decades and remains a leading cause of maternal and fetal deaths worldwide. The findings, published in the journal Circulation, point to dysregulation of a gene called VGLL3 (搜索) in placental trophoblast cells as a central driver of the condition.
Johann Gudjonsson, a dermatologist and professor of immunology at the University of Michigan Taubman Medical Research Institute (搜索), had been investigating why autoimmune diseases are more common in women when a hallway conversation with colleagues in cardio-obstetrics shifted his focus. Ashley Bartell, an OB-GYN specializing in cardio-obstetrics, described the difficulty clinicians face in distinguishing between autoimmune disorders and preeclampsia (搜索).
"The first thought that came into my mind was, I gotta take a look at this, there's gotta be something there," Gudjonsson said. "It was a lightbulb moment."
The VGLL3 (搜索) Connection
Gudjonsson's team had previously found that VGLL3 (搜索), a transcription cofactor that acts as an on/off switch for genes involved in cell growth, immune regulation, metabolism, and hormonal signaling, was more highly expressed in the skin of women compared to men. The gene had also been linked to the timing of first menstrual periods and even sexual maturity in Atlantic salmon, suggesting broader reproductive relevance.
To investigate its role in preeclampsia (搜索), scientist Olesya Plazyo, an immunologist with a background in placental biology, performed RNA sequencing on placenta samples provided by Bartell. The team found that VGLL3 (搜索) was generally overexpressed and dysregulated in preeclamptic placentas, confirming patterns seen in existing published datasets.
Using single-cell RNA sequencing technology, the researchers pinpointed that VGLL3 (搜索) overexpression occurs specifically in trophoblast cells—unique cells found only in the placenta that exist at the interface between mother and fetus and interact with immune cells. "That interaction is thought to be crucial in developing preeclampsia (搜索)," Plazyo said.
Experimental Validation Across Multiple Models
The research team employed multiple experimental models to validate their findings, including in vitro cell culture, human placental tissue samples, and mouse models.
"We kind of wanted to look at all the different angles to be able to say, okay, yes, we have something here—it's not just like a fluke or one model system that doesn't represent what happens in real life," Plazyo explained.
In mouse models, overexpression of VGLL3 (搜索) caused high blood pressure, while inhibition of the protein or deletion of the VGLL3 gene resulted in normal, healthy pregnancy. In cell culture and tissue samples, the team confirmed that VGLL3 controls genes involved in blood vessel development, cell growth and differentiation, and immune responses.
"I think of it almost like a thermostat that is kind of stuck at the high level," Gudjonsson said. "These are all normal biological processes that VGLL3 (搜索) regulates but then sends into overdrive when it's dysregulated."
Gudjonsson acknowledged study limitations, noting that "it takes a long time to generate these mouse models, and mice are not exactly humans."
A Condition with Few Answers
Preeclampsia (搜索) is typically characterized by high blood pressure during pregnancy, with symptoms that may include headaches, shortness of breath, nausea, and confusion. Current guidelines state that preeclampsia occurs after 20 weeks of gestation, with patients requiring multiple blood pressure readings above 140/90. Severe complications can result in preterm birth and even death of both mother and fetus.
There is no treatment or cure beyond managing the pregnancy through delivery. Even then, delivery is not a cure, as Bartell emphasized: preeclampsia (搜索) leads to a lifelong risk for heart disease, stroke, and death.
In 2023, the FDA approved a blood test that detects sFLT-1 (搜索), a protein involved in vascular dysregulation and one of the key biomarkers of preeclampsia (搜索), along with another biomarker to predict which patients might be at risk. However, while these tests may help identify preeclampsia, they do not explain the underlying mechanisms driving trophoblast dysfunction.
"It's exciting that we are now getting some ways to open that black box. That's what VGLL3 (搜索) really is to me," Bartell said.
The Path Toward Clinical Translation
The team is advancing further experiments to demonstrate VGLL3 (搜索)'s potential as a biomarker for diagnostics or as a therapeutic target. The ultimate proof will require clinical trials in humans with preeclampsia (搜索) using a drug that would target and modify VGLL3 activity—a milestone that remains years away.
"There's little to indicate that it wouldn't work," Gudjonsson said. "We've targeted this mechanism and shown it can revert many of the features of preeclampsia (搜索). So without a doubt, I think we could prevent it."
Bartell emphasized the broader significance of the work: "That is crucially important because women have historically been excluded from science. To me, this work is an act of advocacy, reversing decades of a lack of mechanistic attention to women and treatments given in and around pregnancy."
She added: "In other areas of medicine we've moved towards precision medicine, leveraging genetics, leveraging biomarkers. It's time for that to come to obstetrics."
The discovery underscores the value of cross-disciplinary collaboration. As Gudjonsson noted, since hypertension is such a dominant symptom, it would have been easy to have tunnel vision on vascular symptoms and not dig any deeper. The breakthrough emerged precisely because researchers from dermatology, cardiology, and obstetrics joined forces to investigate an unexpected connection.