Study on the role of Sox17 implicated in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is characterized by molecular heterogeneity and complicated pathology in multiple tissues, and remains incurable without general therapeutics. Unexpectedly, a recent large-scale genomic study identified a common risk variant in the enhancer region of Sox17, an endothelial-specific transcription factor, in 60% of patients with PAH, suggesting impaired Sox17 expression as a possible cause of PAH. Rare coding variants in Sox17 were also found in familial PAH. However, how Sox17 variants might contribute to PAH is unknown. To know the role of Sox17 in PAH development, we deleted endothelial Sox17 in adult mice and maintained them under hypoxia for 3 weeks for triggering PAH. PAH phenotypes were evaluated by assessing vascular pathology, inflammation, and cardiac remodeling. Pulmonary arterial pressure was measured using intracardiac hemodynamic catheter. For transcriptomic profiling, we performed in vivo RNA sequencing using endothelial-specific RiboTag system. We examined explanted lung tissues from PAH patients and control subjects. Sox17 levels in pulmonary arterial endothelial cells (ECs) were repressed in tissue samples from a portion of PAH patients compared with non-PAH controls. In mice, Sox17 deficiency did not induce PAH spontaneously, but hypoxia-triggered PAH with high penetrance and severity. This PAH featured hypermuscularization and EC hyperplasia in lung arterioles, pulmonary inflammation, right ventricular hypertrophy, and elevated pulmonary arterial pressure persistent even after long rest in normoxia. Mechanistically, transcriptomic profiling predicted activation of c-Met signaling in Sox17-deficient lung ECs under hypoxic stress. Importantly, hepatocyte grow factor (HGF), a ligand of c-Met, was upregulated in Sox17-deficient lung ECs. Pharmacologic inhibition of c-Met together with a vasodilator effectively attenuated pulmonary cardiovascular pathology, even in mouse subjects with established PAH. Of clinical relevance, HGF levels in pulmonary arterioles were increased in 6 of 7 PAH patients. Consistent with a common risk variant in the Sox17 locus, Sox17 levels in pulmonary arterioles were lower in some PAH patients. HGF levels upregulated by Sox17 deficiency confer a susceptibility to PAH triggered by hypoxia in mice. Given the high HGF levels prevalent in PAH patients, HGF/c-Met signaling could be a general druggable target for PAH treatment.