Scientists discover potential cause of enigmatic vascular disease that mainly affects women

Mount Sinai researchers have identified a key factor in a blood vessel disorder known as fibromuscular dysplasia (FMD) that affects up to 5 percent of the adult population and can lead to high blood pressure, heart attack or stroke.

In a study published on September 13 in Cardiovascular research on natureThe team said that changes in the UBR4 gene played an important role as a key factor in FMD. They suggested that this discovery could be an important step towards developing a therapeutic approach for this disease.

“Although fibromuscular dysplasia was first recognized more than 80 years ago, until now very little was known about its causes, pathobiology or possible treatment,” says Jason Kovacic, MD, PhD, professor of medicine (cardiology) at the Icahn School of Medicine at Mount Sinai and senior author of the study.

“By creating the first mouse model, we have gained crucial insights into the processes that trigger FMD, including the role of the protein-coding gene UBR4 and its associated gene expression supernetwork that regulates vascular function in the body.”

Fibromuscular dysplasia is characterized by abnormal cell growth in the walls of arteries, including the carotid, renal, and coronary arteries. Although anyone can develop this disease, it has a distinct gender prevalence, affecting women in approximately 90% of cases. Unlike other vascular diseases such as atherosclerosis, FMD is not caused by plaque buildup, and many people are unaware that they have it.

Depending on which artery is affected, it can lead to serious medical problems, including aneurysm (bulging and weakening of the artery), dissection (tearing of the artery wall), stroke, and heart attack. The restricted blood flow from FMD can also lead to high blood pressure, pulsatile tinnitus (ringing in the ears that occurs with each heartbeat), and migraines.

The Mount Sinai team undertook the DEFINE-FMD study to better understand the disease, which is suspected to have a strong genetic component. The researchers used skin biopsies from 83 women with FMD and 71 healthy control women to obtain and culture fibroblast cells, which then underwent genetic sequencing to identify genetic differences between the patients and their matched healthy controls.

The application of advanced statistical methods known as “systems biology” has enabled scientists to create the first-ever mouse models that recapitulate aspects of the disease in humans and to uncover important insights into its causal pathways and driving factors.

“These results include the discovery that changes in UBR4 levels, which cause significant changes in the expression levels of other genes in the FMD-associated supernetwork, collectively led to major changes in vascular cell function,” said co-author Jeffrey W. Olin, DO, professor of medicine (cardiology) at Icahn Mount Sinai and an internationally recognized expert in the field of vascular medicine.

“These alterations in turn led to demonstrable widening of the arteries in mice, which is one of the hallmarks of FMD in humans.”

By identifying a gene and its genetic regulatory network that appear to be responsible for a significant portion of the heredity of foot-and-mouth disease, scientists believe they have taken a major step toward a therapeutic solution.

“Our study opens the door to targeted modulation of UBR4 and its disease-related gene regulatory network, which could hold tremendous promise for the many people, particularly women, affected by this disease,” Dr. Kovacic said.

“These exciting results encourage us to continue our work with colleagues around the world to shed light on a disease that, until now, has been largely a blank slate.”