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signaling that promotes mitochondrial function and attenuates PAH development via HIF2\u03b1 inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Sox17 expression was reduced in PAH tissues (rodent models and from patients). Chronic hypoxic pulmonary hypertension was exacerbated by mice with conditional Tie2-Sox17 (Sox17 \u00a0EC\u2212\/\u2212) deletion and attenuated by transgenic Tie2-Sox17 overexpression (Sox17 \u00a0Tg). On the basis of untargeted proteomics, metabolism was the top pathway altered by SOX17 deficiency in PAECs. Mechanistically, we found that HIF2\u03b1 concentrations were increased in the lungs of Sox17 \u00a0EC\u2212\/\u2212 and reduced in those from Sox17 \u00a0Tg mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2\u03b1 overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16\u03b1-hydroxyestrone (16\u03b1OHE; a pathologic estrogen metabolite)\u2013mediated repression of SOX17 promoter activity, Sox17 \u00a0Tg mice attenuated 16\u03b1OHE-mediated exacerbations of chronic hypoxic pulmonary hypertension. Finally, in adjusted analyses in patients with PAH, we report novel associations between a SOX17 risk variant, rs10103692, and reduced plasma citrate concentrations (n\u2009=\u20091,326).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Cumulatively, SOX17 promotes mitochondrial bioenergetics and attenuates PAH, in part, via inhibition of HIF2\u03b1. 16\u03b1OHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202203-0450oc","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T13:56:48Z","timestamp":1678715808000},"page":"1055-1069","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":39,"title":["SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of 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