Jason T. Boehme, Sanjeev A. Datar, Xutong Sun, Wenhui Gong, Qing Lu, Jamie Soto, Michael A. Smith, Alejandro E. Garcia-Flores, Gary W. Raff, TingWang, Emin Maltepe, Stephen M. Black, Jeffrey R. Fineman
University of California San Francisco. Florida International University. University of California Davis.
United States
Scientific Reports
Sci Rep 2025; 15:
DOI: 10.1038/s41598-025-99062-0
Abstract
In patients with congenital heart disease, the development of pulmonary arterial hypertension (PAH) is based on vascular exposure to abnormal hemodynamic forces. In our work using a large animal model of increased pulmonary blood flow and pressure, we have previously described a pattern of alterations to vascular cell metabolism, mitochondrial function, and mitochondrial redox signaling, paralleling changes in advanced pulmonary vasculopathy states. Based on our findings and emerging literature, we believe that endothelial mitochondria play a central role in integrating and relaying pathologic mechanotransductive signals in abnormal pulmonary hemodynamics. In this manuscript, we demonstrate that exposure of the pulmonary vascular endothelium to aberrant mechanical forces increases production of mitochondrial reactive oxygen species (ROS) and stabilizes the transcription factor Hypoxia Inducible Factor-1α (HIF-1α), and that these changes are associated with impaired endothelial production of Nitric Oxide (NO). We validate that the mitochondrial antioxidant 10-(6′-ubiquinonyl)decyltriphenylphosphonium bromide (MitoQ) can reverse these alterations in vitro, and evaluate the effects of MitoQ treatment in vivo utilizing our large animal shunt model. We find that MitoQ therapy in pulmonary overcirculation decreases the production of mitochondrial ROS, diminishes the mechanically-induced stabilization of HIF-1α, and partially restores vascular reactivity by rescuing endothelial NO production. These findings raise exciting prospects concerning shared pathophysiologic mechanisms and possible common therapeutic targets amongst PAH etiologies.
Category
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes