Unraveling Nonenzymatic Nitric Oxide Production and Its Impact on Pulmonary Hypertension

Phenotypic transition of pulmonary artery smooth muscle cells (PASMCs) under hypoxic conditions, which in turn causes increased proliferation and migration capacity, is an important pathological process in Hypoxic pulmonary hypertension (HPH). Although research on the phenotypic transition of PASMCs has been ongoing, little is known about the specific molecular mechanisms underlying this process.

Activin-A is elevated in pulmonary arterial hypertension (PAH) patients, and reportedly suppresses BMPR-II. This suggests one mechanism of action for PAH drug, sotatercept, an activin-ligand trap. However, we were unable to confirm that activin-A reduces BMPR-II in pulmonary endothelial cells. Thus, it seems unlikely that sotatercept influences BMPR-II or PAH via this mechanism.

ACE2 has shown effectiveness in treating pulmonary hypertension in multiple animal models and has some promise in early human trials. The key barrier to translation is that enzymatically active ACE2 is difficult to manufacture and exhibits a short half-life in humans, making chronic administration challenging.

Pulmonary arterial endothelial and smooth muscle cell homeostasis is regulated through the bone morphogenetic protein (BMP) and transforming growth factor beta (TGF-β) receptor pathways. Pathway imbalance results in pulmonary hypertension (PH). Each pathway has ligands and modulators influencing this balance. How these pathways differ in pediatric PH patients is unknown.