Sox17 Deficiency Promotes Pulmonary Arterial Hypertension via HGF/c-Met Signaling

Chan Soon Park, Soo Hyun Kim, Hae Young Yang, Ju Hee Kim, Ralph Theo Schermuly, Ye Seul Cho, Hyejeong Kang, Jae Hyeong Park, Eunhyeong Lee, Hyeon Jin Park, Jee Myung Yang, Tae Wook Noh, Seung Pyo Lee, Sun Sik Bae, Jinju Han, Young Seok Ju, Jun Bean Park, Injune Kim

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: In large-scale genomic studies, Sox17, an endothelial-specific transcription factor, has been suggested as a putative causal gene of pulmonary arterial hypertension (PAH); however, its role and molecular mechanisms remain to be elucidated. We investigated the functional impacts and acting mechanisms of impaired Sox17 (SRY-related HMG-box17) pathway in PAH and explored its potential as a therapeutic target. Methods: In adult mice, Sox17 deletion in pulmonary endothelial cells (ECs) induced PAH under hypoxia with high penetrance and severity, but not under normoxia. Results: Key features of PAH, such as hypermuscularization, EC hyperplasia, and inflammation in lung arterioles, right ventricular hypertrophy, and elevated pulmonary arterial pressure, persisted even after long rest in normoxia. Mechanistically, transcriptomic profiling predicted that the combination of Sox17 deficiency and hypoxia activated c-Met signaling in lung ECs. HGF (hepatocyte grow factor), a ligand of c-Met, was upregulated in Sox17-deficient lung ECs. Pharmacologic inhibition of HGF/c-Met signaling attenuated and reversed the features of PAH in both preventive and therapeutic settings. Similar to findings in animal models, Sox17 levels in lung ECs were repressed in 26.7% of PAH patients (4 of 15), while those were robust in all 14 non-PAH controls. HGF levels in pulmonary arterioles were increased in 86.7% of patients with PAH (13 of 15), but none of the controls showed that pattern. Conclusions: The downregulation of Sox17 levels in pulmonary arterioles increases the susceptibility to PAH, particularly when exposed to hypoxia. Our findings suggest the reactive upregulation of HGF/c-Met signaling as a novel druggable target for PAH treatment.

Original languageEnglish
Pages (from-to)792-806
Number of pages15
JournalCirculation Research
Volume131
Issue number10
DOIs
StatePublished - 28 Oct 2022

Keywords

  • RNA
  • endothelial cells
  • hypoxia
  • pulmonary arterial hypertension
  • sequence analysis

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