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.
Figure 1: SN-A is an important gene regulatory co-expression supernetwork governing 1412 FMD.
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).
Figure 2: Visual representation of SN-A, its GO terms, and green and cyan sub-networks.
a, Visual representation of SN-A (complete list of all genes in SN-A is provided in Supplementary Table 4). The top 14 key drivers are labeled as indicated (complete list of SN-A key drivers is provided in Supplementary Table 6). b, Top 10 GO terms (by Bonferroni P value) of genes in SN-A (full results in Supplementary Table 5). c, Alternate visual representation of SN-A. The top 14 key drivers are labeled as indicated. Note that the current software used to create network visualizations does not permit all genes in each network to be represented, and less than half of the 775 genes in SN-A are shown in either 2a or 2c. d, Visualization of the green network. The green network is one of the 4 networks that comprise SN-A and includes UBR4, which is indicated by a red arrow. e, Visualization of the cyan network. The cyan network is another of the 4 networks that comprise SN-A. Note that of the 4 networks that comprise SN-A, three are quite small. Specifically, and as stated in Table 2, green has 418 genes (including UBR4), but cyan, light cyan and tan have only 136, 78 and 143 genes respectively. Mainly due to size, it is only technically possible to create network visualizations for the green and cyan modules.
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