Uncovering an Early Driver of Pulmonary Arterial Hypertension

“While dysfunction in the inner lining of the blood vessels is recognized as a critical early driver of PAH, the mechanism that locks these endothelial cells into a disease-causing state has remained largely unknown,” says Malik Bisserier, Ph.D., assistant professor of cell and molecular physiology and senior author on the study. “In our research, we found that the gene EP300 plays a central role in driving early endothelial inflammation, oxidative stress, and abnormal proliferation. By focusing on early molecular changes that drive blood vessel damage, rather than later consequences, these findings may also support earlier and more personalized treatment approaches aimed at slowing disease progression or even preventing disease onset.”

The researchers uncovered that EP300 levels and histone H3K27 acetylation, a chemical change that helps control whether certain genes are turned on or off, were higher in both people with PAH and experimental models of the disease. Mechanistically, EP300 influences neuropilin-1 (NRP-1), a cell-surface protein that helps guide blood vessel growth, by changing how genes are switched on or off, connecting gene regulation to inflammation and metabolism.

“Although we knew that changes in gene regulation would affect blood vessels in PAH, we were surprised to find that EP300 plays a much bigger role than expected—acting as a hub that connects many of the disease’s key processes,” explains Dr. Bisserier. “Finding that EP300 directly regulates NRP-1 was especially important because of its established link to disease severity in patients. This connection helped link our laboratory findings to real-world patient data, making the results more relevant to clinical care.”

Although the study findings are pre-clinical, Dr. Bisserier stresses that they showcase methods that could better differentiate PAH patients to help estimate disease risk and drive treatment decisions. 

“PAH is a complex condition. Patients differ in how the disease starts, how fast it progresses, and how they respond to treatment. Improving outcomes will require earlier detection and a better understanding of the biological changes driving disease in each patient,” says Dr. Bisserier. “Studies like this highlight how identifying specific molecular and gene regulation changes can help guide more precise and personalized treatment approaches rather than relying on uniform therapies for all patients.”