Abstract 12319: 16alpha-Hydroxyestrone Downregulates SOX17 During the Development of Pulmonary Arterial Hypertension

Abstract

Introduction: Sexual dimorphism in pulmonary arterial hypertension (PAH) is attributed, in part, to estrogen signaling. 16α-hydroxyestrone (16αOHE) is considered a major contributor to PAH pathogenesis. Recent genetic studies have also suggested that deficiency of SOX17, an endothelial cell (EC)-specific transcription factor, contributes to PAH risk. While functional studies of SOX17 are absent, we hypothesized that 16αOHE contributes to PAH, in part, via, SOX17 downregulation. Methods/Results: Sox17 expression was reduced in 3 animal PAH models and in human pulmonary artery ECs (HPAECs) isolated from patients with PAH (vs controls). Inducible Tie2-specific Sox17 knockout ( Sox17 EC-/- ) mice exhibited increased right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and PA wall thickness (PAWT) after chronic hypoxia (CH) (Fig 1A). Inducible Tie2- Sox17 transgenic overexpressing ( Sox17 Tg ) mice attenuated CH-induced PH (Fig 1B). While not evident across murine sex, Sox17 expression was increased in baseline lungs from male compared to female rats. Supporting in silico evidence of estrogen response elements (ERE) on the SOX17 promoter, HPAECs exposed to 16αOHE reduced SOX17 expression and promoter luciferase activity via ERα, which was partly negated by serial ERE mutagenesis (Fig 1C ) . Lungs from ERα loss-of-function mutant rats (vs control) confirmed in vivo reductions of Sox17 expression. Sox17 Tg mice attenuated 16αOHE-mediated PH after CH (Fig 1D). To translate these data, we identified a functional coding SNP in the ESR1 gene (encoding ERα), rs746432, previously shown to reduce transcriptional activity of ERα. The SNP was associated with reduced pulmonary vascular resistance in patients with PAH (n=702, Fig 1E) in adjusted analyses. Conclusion: Validating genetic studies, SOX17 deficiency augments preclinical PAH. 16αOHE mediates PH development via downregulation of SOX17, linking SOX17 genetics with the observed sexual dimorphism.