How Mitigating the Damaging Impact of High Shear Stress on Blood Vessels Could Stop PAH Progression
by Amanda Chase, PhD
January 22, 2025
Pulmonary arterial hypertension (PAH) is a serious condition where the blood pressure in the lung (pulmonary) arteries becomes progressively elevated, often leading to heart failure. Unfortunately, the underlying mechanisms driving PAH remain poorly understood.
In a recent Arteriosclerosis, Thrombosis, and Vascular Biology publication, Stanford researchers, led by co-first authors Tsutomu Shinohara and Jan-Renier Moonen and senior author Marlene Rabinovitch focused on how high sheer stress (HSS), a force caused by increased blood flow in small pulmonary arteries, damages the delicate cells lining these vessels. Using innovative laboratory techniques and a mouse model, their work showed that HSS triggers a harmful process called endothelial-to-mesenchymal transition (EndMT). This process causes blood vessel cells to lose their normal function, promoting narrowing of the arteries, and causing progression of PAH.
Overview of how high shear stress can contribute to EndMT and progression of PAH.
The researchers explored whether restoring certain factors could prevent narrowing of the lung arteries, by focusing on a molecule called ERG that helps maintain healthy blood vessels. This study showed that HSS reduces ERG levels, leading to EndMT and the progression of PAH. The team then developed a novel therapy using a viral delivery system engineered to restore ERG specifically to the vulnerable cells liningPi the arteries of the lung. They used this therapy to deliver ERG in a mouse model where HSS in the arteries of the lung causes PAH. They found that the therapy reduced EndMT and prevented the progression of PAH.
This important study provides new insights into how high blood flow harms the lung arteries and shows that restoring ERG might be a promising approach to treat or prevent PAH, especially in conditions linked to congenital heart defects that create HSS in the lung arteries.
This important research was accomplished with a collaborative team, including groups from Austria (Medical University of Graz), Japan (Nagoya City University Graduate School of Medicine Sciences and Mie University Graduate School of Medicine), and Germany (University Medical Center Hamburg-Eppendorf). Other Stanford Cardiovascular Institute researchers include Yoon Hong Chun, Kenichi Okamura, Jason Szafron, Jordan Kaplan, Aiqin Cao, Lingli Wang, Shalina Taylor, Sarasa Isobe, Melody Dong, Alison Marsden, and Jesse Engreitz.
Dr. Marlene Rabinovitch