Shedding light on pulmonary arterial hypertension
By Amanda Chase, PhD
November 20, 2020
Translational science is affording us an era of improved understanding and treatment of many diseases, including fatal diseases. Improved models and tools allow researchers the chance to understand these fatal diseases to develop and provide treatments for the underlying cause of disease rather than just treating to control symptoms. Recent work by a Stanford group, led by first authors Lea Steffes, MD, and Alexis Froistad and senior author Maya Kumar, PhD, highlights how new models and innovative technologies can combine to uncover disease mechanisms of pulmonary arterial hypertension (PAH).
PAH is a fatal disease that is characterized by progressive narrowing of the arteries in the lungs. Narrowing is a result of abnormal cells (neointima cells) accumulating in the vessel, and it causes the heart to work harder to pump blood through the lungs. This leads to the heart muscle weakening and, eventually, failing. PAH is considered to be a rare disease, with 500-1000 new cases per year in the US, occurring most commonly in women between the ages of 30-60. Currently, there are only limited therapies, mostly directed at reducing symptoms, and no cure.
In their recent Circulation publication, the Stanford research team is able to use novel tools to address several unknown critical to understanding underlying mechanisms of PAH to lead to potential treatments. For example, the origin of cells involved in artery narrowing was unknown, as were the steps in pulmonary artery remodeling and the signals controlling those remodeling steps. Understanding all of those unknowns is the first step to finding a cure for PAH.
First, the team was able to establish a mouse model of PAH that reproduces key features of human PAH. Having a model is critically important because patients often present with advanced disease, making it difficult to study early stages of the disease. This mouse model was used in combination with innovative techniques to demonstrate that the cells originated from vascular smooth muscle cells of the artery wall, not from the endothelium, which informed a point of debate in the field. The researchers were also able to define both temporally and spatially distinct steps in the development of pulmonary artery formation. Understanding the developmental stages of pulmonary arteries will, in the future, provide targets for PAH treatments.
Finally, they showed that cells expressing a gene called Notch3 was the major subset of cells that abnormally migrated to result in a narrowed vessel, and that process occurs in a Notch-dependent manner. This finding provides a potential target for treatments to prevent vessel thickening characteristic of PAH. Together, this Stanford team of researchers was able to open the door for future studies to offer new avenues for therapy development.
Other Stanford affiliated authors are Adam Andruska, Mario Boehm, Madeleine McGlynn, Fan Zhang, Wenming Zhang, David Hou, Xuefei Tian, Lucile Miquerol, Kari Nadeau, Ross Metzger, and Edda Spiekerkoetter.