How a Y chromosome gene may shape the course of heart valve disease microbiologystudy

A study led by bioengineers at the University of California San Diego sheds new light on how a type of heart valve disease, called aortic valve stenosis, progresses differently in males and females. The research reveals that this sex-based difference can be traced to a gene on the Y chromosome.

The discovery, published in Science Advances, not only showcases the critical need to understand how sex chromosomes influence disease progression, but it also paves the way for treatments that could be tailored to a patient’s biological sex.

“When we study sex differences in disease, we help everyone,” said study senior author Brian Aguado, professor in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering.

“If we’re serious about improving health outcomes for all patients, we need to understand how disease works differently in both males and females.”

Aguado’s work is part of a growing body of research exploring the role of sex as a biological variable in disease. Many studies have been conducted primarily on male patients or male-derived cells, under the assumption that sex differences were unimportant.

But over the past decade, scientists and funding agencies have pushed for a more comprehensive approach—one that accounts for the influence of X and Y chromosomes in shaping disease.

That shift is already yielding insights that could transform how doctors diagnose and treat diseases like aortic valve stenosis.

“Our research is showing that we need to look at your chromosome makeup to figure out the best treatment for you. The one-size-fits-all approach often does not work,” said Aguado. “By supporting sex difference research, we can make medicine better for more than just a subset of the population.”

Aortic valve stenosis, or AVS, is a life-threatening disease in which the heart’s aortic valve stiffens, impeding blood flow. This forces the heart to work harder to pump blood and increases the risk of heart failure. In males and females, the disease initially manifests differently: males develop calcium buildup in the heart valve early on, while females experience stiffening due to the formation of fibrotic tissue.

“In both cases, the valve stiffens, but for different reasons,” said study first author Rayyan Gorashi, a bioengineering Ph.D. candidate in Aguado’s lab.

Now, researchers have identified a Y chromosome-linked gene, UTY (ubiquitously transcribed tetratricopeptide repeat containing Y-linked), as a key driver of valve calcification in males.

Digging into the sex differences of early-stage valve disease

In the early stages of AVS, specialized heart valve cells, called valvular interstitial cells, become abnormally activated. In females, these cells primarily transform into smooth muscle-like cells called myofibroblasts, which stiffen the valve through fibrosis. But in males, these myofibroblasts take an additional step: they differentiate into bone-like cells that generate calcium nanoparticles, leading to valve calcification.

“This study highlights the importance of digging into the sexual dimorphism that’s seen in aortic valve stenosis,” said Gorashi.

“Since the molecular pathways driving this disease are different in males and females, understanding these sex-based mechanisms can allow us to create sex-specific treatment options for patients down the line.”

To explore these molecular pathways, the researchers turned to biomaterials. They engineered a hydrogel that mimics the microscopic structures and stiffness of aortic valve tissue, then used it to culture male and female heart valve cells.

On this tissue-like surface, they saw the same sex-based differences observed in actual valve tissue—female cells transformed into myofibroblasts, while male cells continued down the path to becoming bone-like cells. But when the cells were cultured on a standard Petri dish, these differences were absent.

“The male and female cells essentially looked the same in a standard Petri dish,” Aguado explained.

“However, when we grew them in an engineered microenvironment that resembled actual valve tissue, we started to see sex-based differences in cellular behaviors. This demonstrates the importance of using bio-inspired tools to capture physiological differences that traditional cell culture methods miss.”

To further probe the mechanisms driving these differences, the researchers incorporated nanoparticles into the hydrogel to simulate calcification sites within diseased tissue. They found that the presence of these particles amplified the sex-based differences even further. This finding reinforces the idea that the microenvironment plays a critical role in how AVS unfolds.

Roles of the sex chromosomes

From there, the researchers turned their attention to genetic regulators of this process and focused on the Y chromosome. By performing gene knockdowns, they identified UTY as a key gene in influencing how male heart valve cells responded to their environment, pushing them toward a calcified state.

“It’s exciting how we can use engineered tools to uncover biological mechanisms that have been previously overlooked,” said Aguado. “The X and Y chromosomes have traditionally been viewed primarily as determinants of biological sex, but they’re much more than that. They contain genes that affect how cells function in ways we’re only beginning to appreciate.”

“There’s also much more work that needs to be done to investigate the mechanisms at play on the X chromosome,” Gorashi added. “It would be interesting to dig deeper like what we have done here, using specialized biomaterials and looking at nanoscale cues in valve tissue, to elicit the other half of the story.”

The team’s next step is to explore how UTY might be targeted with drugs. They are now working to identify potential drug combinations that specifically target early-stage AVS processes in males and females.

“We’re diving into the basic science of how sex chromosomes influence not just how disease develops, but how cells respond to treatment,” said Aguado. “By figuring out these sex-dependent mechanisms, we can develop therapies that are more effective for all people.”