image: a, Catheter-based angiographic image of typical multifocal FMD (‘string-of-beads’) affecting the renal artery. b, Catheter-based angiographic image of FMD in a different patient 1414 demonstrating typical multifocal renal FMD with aneurysmal involvement (arrow). Image in b reproduced with permission.77 c, Overview of study and data analysis workflow. DGE, differential gene expression; GWAS, genome-wide association study; WGCNA, weighted gene co-expression network analysis. The human schematic was from Servier Medical Art, which is licensed under CC BY 4.0. d, Volcano plot of primary fibroblast DGE between FMD cases versus matched controls. Selected genes were individually labeled (full results in Supplementary Table 1). Blue and purple data points represent the 349 transcripts that were significantly different after multiple comparison testing. e, Top 10 GO terms for terms based on P values of DGE between FMD cases and matched controls for genes showing upregulated gene expression, with these 10 GO terms all showing positive enrichment (full results in Supplementary Table 2). GOBP, GO biological process; GOMF, molecular function; GOCC, GO cellular component. f, Top 10 GO terms for terms based on P values of DGE between FMD cases and matched controls for genes showing downregulated gene expression, with these GO terms showing 2 with negative fold enrichment and 8 with positive enrichment (full results in Supplementary Table 3).
Credit: Mount Sinai Health System
Mount Sinai researchers have identified a key driver of a blood vessel disorder known as fibromuscular dysplasia (FMD) which affects up to five percent of the adult population and can lead to high blood pressure, heart attack, or stroke.
In a study published September 13 in Nature Cardiovascular Research, the team said changes in the gene UBR4 played an important role as a key driver of FMD. They suggested the discovery could be an important step toward developing a therapeutic approach for the disorder.
“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 gained critical insights into the processes that trigger FMD, including the role of the protein coding gene UBR4 and its associated gene expression supernetwork which regulates vascular function in the body.”
Fibromuscular dysplasia involves abnormal cell growth in the walls of the arteries, including the carotid, renal, and coronary arteries. Though anyone can develop the condition, it has a distinct sexual bias, affecting women in about 90 percent of cases. Unlike other vascular diseases such as atherosclerosis, FMD is not caused by a build-up of plaque, and many people are unaware they have the disorder. Among the serious medical conditions it can lead to—depending on which artery is affected—are aneurysm (bulging and weakening of the artery), dissection (tearing of the arterial wall), stroke, and heart attack. Restricted blood flow from FMD can also result in high blood pressure, pulsatile tinnitus (whooshing sound in the ears that occurs with each heart beat), and migraine headaches.
Mount Sinai undertook the DEFINE-FMD study to gain a better understanding of this disease, which was suspected of having a strong genetic component. Researchers used skin biopsies from 83 women with FMD as well as from 71 healthy female controls to obtain and grow fibroblast cells, which then underwent gene sequencing to pinpoint the genetic differences between patients and the matched healthy controls. Applying advanced statistical methods known as “systems biology” enabled the scientists to create the first-ever mouse models that recapitulated certain aspects of the disease in humans, and to uncover important insights into its causal pathways and disease drivers.
“These insights included the finding 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,” explains co-author Jeffrey W. Olin, DO, Professor of Medicine (Cardiology) at Icahn Mount Sinai and an internationally known expert in the field of vascular medicine. “These alterations in turn led to a demonstrable widening of the arteries in mice, which is one of the features of FMD in humans.”
By identifying a gene and its gene regulatory network that appear to account for a significant portion of FMD heritability, 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-relevant gene regulatory network, and that could hold tremendous promise for the many people, particularly women, with this condition,” emphasizes Dr. Kovacic. “These exciting findings are encouraging us to continue our work with colleagues around the world to shed further light on a disease which until now was largely a blank slate.”
Funding for this study was supported by grants from the National Heart, Lung, and Blood Institute at the National Institutes of Health and additional philanthropic support.
Mount Sinai Is a World Leader in Cardiology and Heart Surgery
Mount Sinai Fuster Heart Hospital at The Mount Sinai Hospital ranks No. 1 in New York and No. 4 nationally for cardiology, heart, and vascular surgery, according to U.S. News & World Report®. It also ranks No. 1 in New York and No. 6 globally according to Newsweek’s “The World’s Best Specialized Hospitals.”
It is part of Mount Sinai Health System, which is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. We advance medicine and health through unrivaled education and translational research and discovery to deliver care that is the safest, highest-quality, most accessible and equitable, and the best value of any health system in the nation. The Health System includes approximately 9,000 primary and specialty care physicians; 11 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 39 multidisciplinary research, educational, and clinical institutes. Hospitals within the Health System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals” and by U.S. News & World Report's® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report's® “Best Hospitals” Honor Roll for 2024-2025.
For more information, visit https://www.mountsinai.org or find Mount Sinai on Facebook, Twitter and YouTube.
Journal
Nature Cardiovascular Research
Method of Research
Experimental study
Article Title
Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia
Article Publication Date
13-Sep-2024