Scientists at Michigan Medicine have uncovered how a common genetic variant linked to high blood pressure causes long-term changes in blood vessel structure—raising the risk of heart attacks and strokes.
Their findings, published in the Journal of Clinical Investigation, reveal a key role for an enzyme called JMJD3 in regulating blood pressure and vascular health.
The research may lead to new treatments tailored to individuals with specific genetic risks.
High blood pressure, or hypertension, doesn’t just affect numbers on a monitor—it changes the very structure of the blood vessels through a process known as arterial remodeling.
This occurs when the smooth muscle cells in blood vessel walls adapt in response to constant pressure, making the vessels stiffer and narrower over time. These changes can lead to life-threatening events such as heart attacks, strokes, and organ damage.
Researchers focused on the enzyme JMJD3 (Jumonji domain-containing protein-3), which had previously been linked to blood pressure regulation in large genetic studies. JMJD3 affects the behavior of smooth muscle cells by controlling how two specific endothelin receptors—called receptor-A and receptor-B—are expressed.
Endothelin is a small protein that acts like a chemical messenger, helping blood vessels tighten or relax. For blood pressure to stay balanced, there needs to be a healthy interaction between receptor-A, which constricts blood vessels, and receptor-B, which helps them dilate. JMJD3 plays a crucial role in maintaining this balance.
In their study, the team reduced JMJD3 levels in mice and found that this led to lower receptor-B levels and higher receptor-A levels. The result? Blood vessels became more constricted, blood pressure rose, and over time, structural changes occurred in the arteries—setting the stage for serious cardiovascular problems.
“This shows JMJD3 is central to managing the balance of endothelin receptors that keep blood pressure in check,” said Dr. Kevin Mangum, lead author and vascular surgery resident at the University of Michigan Health.
The researchers then took their investigation a step further by focusing on a common genetic variant called rs62059712, found in about 90% of people. This variant was previously linked to high blood pressure, but the mechanism was unclear.
The study found that people with this variant tend to have lower JMJD3 expression, creating a “double hit” effect—higher blood pressure and harmful blood vessel remodeling.
The variant increases levels of the constricting receptor-A while reducing the protective receptor-B, setting off a chain reaction that affects blood vessel tone and structure. Importantly, this process is driven by overactive endothelin-ERK signaling, a pathway known to contribute to vascular disease.
To counteract this, researchers tested a compound called BQ-123, which blocks endothelin receptor-A. In mice lacking JMJD3, BQ-123 reversed hypertension, suggesting it could be used as a targeted therapy for people with the genetic variant.
“For people carrying this common genetic variant, we may one day be able to use personalized treatments to reduce their risk of hypertension and its complications,” said Dr. Katherine Gallagher, senior author and professor at the U-M Medical School. “This could help offset the genetic disadvantage they carry.”
The study opens the door for further research into personalized medicine for cardiovascular conditions. It also demonstrates how analyzing the effects of specific genes—like JMJD3—can help scientists better understand the roots of disease and create targeted interventions.
“With more genetic variants being discovered, our approach could serve as a model for figuring out which ones truly matter, and how to act on them in the clinic,” Gallagher added.
In summary, this research links a common genetic variant to both high blood pressure and long-term vascular damage, identifies a key regulatory enzyme behind this process, and suggests a path to personalized therapies that could improve outcomes for millions at genetic risk.
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The research findings can be found in Journal of Clinical Investigation.
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