Researchers at the Fralin Biomedical Research Institute at VTC have identified a natural protective protein that maintain healthy lung blood vessels. Increasing the expression of this protein in preclinical models of pulmonary arterial hypertension reversed key features of the disease, including pulmonary vascular remodeling and heart dysfunction.
The study in the European Respiratory Journal found that levels of bone morphogenetic protein 3, or BMP3, are significantly reduced in pulmonary arterial hypertension, a rare and progressive disease that causes elevated blood pressure in the lungs and can lead to heart failure.
Researchers used two different methods to increase BMP3 levels, and both methods reversed key features of the disease, including damaged blood vessels and impaired heart function.
The findings reveal a previously unrecognized pathway involved in pulmonary arterial hypertension and point to new treatment strategies aimed at correcting the underlying disease process.
"Pulmonary arterial hypertension remains a devastating disease with limited treatment options," said Yassine Sassi, senior author of the study and an associate professor at Virginia Tech's Fralin Biomedical Research Institute. "Most current therapies focus on managing symptoms or slowing disease progression. What makes this discovery exciting is that it identifies a new therapeutic strategy aimed at restoring a natural protective mechanism that is lost during disease."
Although BMP3 has been studied in bone biology and cancer, this study is the first to identify a role for the protein in pulmonary arterial hypertension.
The researchers discovered that BMP3 is produced by cells in the walls of lung blood vessels. In healthy lungs, BMP3 helps keep blood vessel cells from growing and spreading too aggressively. But in pulmonary arterial hypertension, BMP3 levels fall. Without enough BMP3, blood vessels begin to thicken and narrow, restricting blood flow through the lungs. The study found that BMP3 levels were consistently reduced in lung tissue and blood samples from patients with pulmonary arterial hypertension, as well as in experimental models of the disease.
To test whether restoring BMP3 could counteract disease progression, the researchers used both recombinant BMP3 protein and a lung-targeted gene therapy approach designed to increase BMP3 expression. Both strategies significantly reduced disease severity in multiple preclinical models, improving pulmonary vascular structure and cardiac function.
"This gives us two potential therapeutic paths forward: a biologic therapy and a gene-based approach, both designed to restore a natural protective signal that is lost during disease," said Sassi, who is also an associate professor with the Virginia-Maryland College of Veterinary Medicine's Department of Biomedical Sciences and Pathobiology.
The team also found that circulating BMP3 levels were significantly lower in patients with pulmonary arterial hypertension, suggesting the protein could eventually serve as both a therapeutic target and a biomarker for monitoring disease.
By restoring BMP3 levels, researchers were able to suppress the cellular changes that drive disease progression and reverse key features of the disease in preclinical models.
While additional studies are needed before the approach can be evaluated in patients, the findings identify BMP3 as a promising therapeutic target in a disease for which no currently approved therapy reverses the underlying vascular remodeling.
Sassi and first author Aymen Halouani of the Fralin Biomedical Research Institute have filed a patent application covering BMP3-based therapeutic approaches for pulmonary arterial hypertension.
