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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-1\u03b1 (HIF-1\u03b1), and that these changes are associated with impaired endothelial production of Nitric Oxide (NO). We validate that the mitochondrial antioxidant 10-(6\u2032-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-1\u03b1, 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.<\/jats:p>","DOI":"10.1038\/s41598-025-99062-0","type":"journal-article","created":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T06:18:49Z","timestamp":1746857929000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mechanotransductive stabilization of HIF-1\u03b1 is inhibited by mitochondrial antioxidant therapy in the setting of pulmonary overcirculation"],"prefix":"10.1038","volume":"15","author":[{"given":"Jason T.","family":"Boehme","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeev A.","family":"Datar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xutong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhui","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Soto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro E.","family":"Garcia-Flores","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary W.","family":"Raff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emin","family":"Maltepe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M.","family":"Black","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Fineman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,10]]},"reference":[{"key":"99062_CR1","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1164\/rccm.202302-0327SO","volume":"208","author":"S Johnson","year":"2023","unstructured":"Johnson, S. et al. 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