Endothelial Redox Dysregulation in Pulmonary Arterial Hypertension: Compartmentalized Mechanisms and Therapeutic Implications

Abstract

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy in which endothelial dysfunction drives increased pulmonary vascular resistance and arterial remodeling. Redox signaling is central to endothelial homeostasis, and its disruption in PAH reflects changes in the magnitude, source, and subcellular location of reactive oxygen species (ROS) production, as well as the molecular targets they engage. In healthy endothelium, compartmentalized redox signaling supports adaptive responses while preserving nitric oxide bioavailability. Loss of this spatial control in PAH can convert normally transient redox signals into persistent endothelial dysfunction, although the strength of evidence for this conversion differs substantially between pathways. This review examines how disease-associated stressors reshape endothelial redox signaling through NADPH oxidases, mitochondria, eNOS, iron-dependent chemistry, and nuclear pathways and how these compartments communicate. We also examine emerging circulating markers of redox and endothelial dysfunction and evaluate redox-directed therapies across experimental pulmonary hypertension and PAH. Throughout, we grade each mechanism according to whether it is supported by evidence from human PAH vascular tissue, patient-derived pulmonary arterial endothelial cells, experimental pulmonary hypertension models, and pulmonary endothelial models or by extrapolation from other relevant disease systems, and we identify where compartment-specific evidence is inferred from enzyme localization rather than measured directly. Current evidence supports moving beyond broad antioxidant approaches toward strategies that selectively target pathogenic redox signaling within the relevant endothelial compartment.