Unveiling the role of Jagged2 in hypoxic pulmonary arterial hypertension: A NOX2‐mediated pathway

Hypoxic pulmonary arterial hypertension (PAH) is a severe cardiovascular condition involving vascular remodeling and inflammation. Jagged2 (Jag2) has been implicated in various pathologies but its role in PAH remains unclear. We integrated bioinformatics analysis of transcriptomic data with in vitro and in vivo experiments to investigate Jag2's function in hypoxic PAH. We focused on primary rat pulmonary artery smooth muscle cells (PASMCs) for cellular responses and a rat model for hemodynamic changes. Jag2 was upregulated under hypoxic conditions, promoting PASMC proliferation and migration and inhibiting apoptosis through NADPH oxidase 2 (NOX2)/reactive oxygen species (ROS) signaling. Inhibition of Jag2 ameliorated hemodynamic changes and vascular remodeling in the PAH rat model. Jag2 activation of NOX2/ROS signaling is a critical driver of vascular inflammation and remodeling in hypoxic PAH, suggesting the Jag2/NOX2 axis as a therapeutic target.