They find the answer to why aortic valve stenosis progresses differently in men and women

Traditionally, the X and Y chromosomes have been considered mainly determinants of biological sex, however, many more attributions are beginning to be known, as they contain genes that affect cell functioning and can reveal many clues about pathologies such as aortic valve stenosis.

Aortic valve stenosis (VAS) is considered a life-threatening condition, in which the heart's aortic valve hardens, making it difficult for blood to flow, forcing the heart to work harder to pump blood. All of this increases the risk of heart failure.

On this pathology, a study led by bioengineers from the University of California in San Diego (USA) has been able to confirm that VAS progresses differently in men and women. While calcium builds up in the heart valve early in men, it hardens in women due to the formation of fibrotic tissue.

To explore these molecular pathways, the scientists turned to biomaterials such as a hydrogel that mimics the microscopic structures and stiffness of aortic valve tissue and used it to grow male and female heart valve cells. On this tissue-like surface, they observed the same sex-specific differences seen in real valve tissue: female cells transformed into myofibroblasts, while male cells continued their way to become bone cells. However, when growing the cells in a standard petri dish, these differences were not observed.

"By growing male and female cells in an engineered microenvironment that resembled real valve tissue, we began to observe sex differences in cell behavior. This demonstrates the importance of using bioinspired tools to capture physiological differences that traditional cell culture methods overlook," said Brian Aguado, a professor in the Shu Chien-Gene Lay Department of Bioengineering at UC San Diego's Jacobs School of Engineering, and senior author of the study.

Clues about the differences in VAS

To delve deeper into the mechanisms driving these differences, the researchers incorporated nanoparticles into the hydrogel to simulate calcification points in diseased tissue. They found that the presence of these particles further amplified sex differences. Specifically, the researchers were able to identify a Y-chromosome-linked gene, UTY (ubiquitous transcribed tetratri-hopeptide repeat containing Y-linked), as a key driver of valve calcification in males, and which influenced how male heart valve cells responded to their environment, pushing them into a calcified state.

Another of the uses of this study is the establishment of a hydrogel cell culture platform that allows the interrogation of genes linked to the Y chromosome and their impact on the specific cellular phenotypes of men.

The findings, published in Science Advances, therefore confirm the critical need to understand how sex chromosomes influence disease progression, and pave the way for treatments that could be adapted to the patient's biological sex. "Our research shows that we need to analyze the chromosomal composition of each patient to determine the best treatment, as a universal approach does not always work," concluded Prof. Aguado.