A group of researchers at the University of Kentucky have found a mechanism that would explain why men develop more aortic aneurysms than women.

The study titled “Androgen aggravates aortic aneurysms via suppression of PD-1 in mice,” accompanied by a commentary, was published in June in the Journal of Clinical Investigation, one of the top journals for research on medicine and basic science.

The work was led by Zhenheng Guo, Ph.D., a professor in the Department of Pharmacology and Nutritional Science, and Ming Gong, Ph.D., M.D., a professor in the Department of Physiology, both in the UK College of Medicine, with the support of multiple grants from the National Institutes of Health.

Researchers worked to better understand sex disparities in the development of abdominal aortic aneurysms. They investigated how androgens, male sex hormones like testosterone, affect the development of aortic aneurysms, which are dangerous enlargements of the aorta, the main artery that carries blood from the heart to the rest of the body.

Aortic aneurysms are often asymptomatic until rupture, which have a mortality rate of over 80% and are more prevalent in men. As a consequence, this study aimed to explain the role of androgens in aggravating aortic aneurysms, providing an understanding of how sex-specific differences can contribute to this condition.

Current clinical evidence shows that 80% of people affected by aortic aneurysms are men. To be able to study this condition considering the sex difference, the researchers developed a mouse model with inducible aortic aneurysms.

“Remarkably, none of the female mice developed aortic aneurysms, whereas 70% of male mice had aortic aneurysms,” said Gong.

“We demonstrated that aortic aneurysms were abolished or ameliorated by global androgen deprivation or blockage,” said Xufang Mu, Ph.D, the first author of the paper and a postdoctoral student in Gong’s lab.

This was shown by removing the androgen source in their mouse model both surgically and pharmacologically, which then dramatically reduced the number of aortic aneurysms. Importantly, the aortic aneurysms were restored when the androgen was re-administered.

After confirming that androgens can aggravate aortic aneurysms, the research team decided to explore the specifics of the mechanism by which androgens drive this phenomenon.

“One of our findings, which we believe to be novel, is a mechanism by which androgen suppresses PD-1 expression,” said Guo.

PD-1 is a receptor that has a crucial role in preventing excessive inflammation and modulating immune responses, the mechanisms that the body uses to defend itself against harmful situations and organisms. PD-1 inhibitors keep the body’s T cells — a type of white blood cell — active, allowing them to recognize and destroy cancer cells.

“Targeting PD-1 and its inhibitors are a promising immune checkpoint therapy in treatment for a wide variety of cancers. Unfortunately, targeting PD-1 and its inhibitors has many side effects, including autoimmune myocarditis, pericarditis and vasculitis,” said Guo. “In alignment with these findings, our study also suggests that targeting PD-1 and its inhibitors may cause aortic aneurysms. Thus, some patients with cancer and the risk of developing aortic aneurysms, such as men, those of older age, and those who smoke, might benefit from screenings for aortic aneurysms by ultrasound during immune checkpoint therapy to increase the life-saving potential of this treatment.”

The findings from this study suggest that the presence of high levels of androgens, naturally occurring in males, can downregulate PD-1, increasing inflammation and contributing to the progression of aortic aneurysms, and targeting PD-1 could be a strategy to manage this condition since currently there are no medications for its treatment.

The study brought together researchers from the Department of Pharmacology and Nutritional Sciences and the Department of Physiology in the College of Medicine, Department of Statistics in the College of Arts and Sciences, and the Saha Cardiovascular Research Center at UK, along with the Sacramento Veterans Affairs Medical Center and Vanderbilt University.

The team received support from the Office of the Vice President for Research, the UK Center of Research in Obesity and Cardiovascular Disease, the UK Markey Cancer Center and the UK Flow Cytometry and Immune Monitoring Core Facility.

Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Numbers R01HL125228, R01HL141103, R01HL142973, R01HL164398 and R01HL166225; the National Institute on Deafness and Other Communications of the National Institutes of Health under Award Numbers R01DC014468 and K18DC014050; the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P30GM127211; and the National Cancer Institute of the National Institutes of Health under Award Number P30CA177558. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 

This material is based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.