The secreted glycoprotein neuroblastoma suppressor of tumorigenicity 1 (NBL1) worsens flow-associated pulmonary arterial hypertension (PAH) by inducing endothelial to mesenchymal transition via the transforming growth factor beta (TGF-β)/bone morphogenetic protein (BMP) signaling pathway.

This is according to a new study published in the American Journal of Respiratory Cell and Molecular Biology. These findings suggest that antagonizing NBL1 and rebalancing TGF-β/BMP signaling may be a therapeutic option for congenital heart disease-related PAH.

Congenital heart disease-related PAH is associated with flow-induced vascular remodeling, in which endothelial to mesenchymal transition plays a critical role. 

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It was already known that NBL1 plays a role in PAH related to congenital heart disease, as it aggravates the phenotypic transformation of smooth muscle cells. However, its exact effect on endothelial cells was not clear.

Read more about the pathophysiology of PAH

In the present study, a team of researchers from China explored the potential role of NBL1 in endothelial to mesenchymal transition. They used a new rat model of flow-associated PAH in which the gene coding for NBL1 was knocked out. 

The researchers found that knocking out the Nbl1 gene could effectively attenuate flow-associated PAH by downregulating endothelial to mesenchymal transition. They also showed that NBL1 induced endothelial to mesenchymal transition using human pulmonary artery endothelial cells grown in culture.

“Both in vitro and in vivo experiments supported the imbalance of increased TGF-β and dysregulation of BMP signaling by NBL1,” the researchers wrote.

They found that when they blocked the canonical TGF-β pathway, endothelial function was preserved upon NBL1 stimulation. This led them to conclude that NBL1 exerts its activity via the TGF-β signaling pathway.

PAH related to congenital heart disease is characterized by flow-induced pressure overload, which accelerates the progression of pulmonary vascular remodeling. There are no effective treatments for the disease, and the only current option is lung transplantation.


Wen B, Peng R, Kong P, et al. NBL1 mediates endothelial-to-mesenchymal transition in pulmonary arterial hypertension related to congenital heart disease. Am J Respir Cell Mol Biol. Published online September 28, 2022. doi:10.1165/rcmb.2022-0157OC