SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics

Genetic studies suggest that SOX17 deficiency increases the risk of pulmonary arterial hypertension (PAH). Researchers hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF2α inhibition. Sox17 expression was reduced in PAH tissues, and chronic hypoxic pulmonary hypertension was exacerbated by mice with conditional Tie2-Sox17 deletion and attenuated by transgenic Tie2-Sox17 overexpression. Mechanistically, SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2α overexpression. 16αOHE mediated PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH.