SOX17 in pulmonary arterial hypertension: from development to clinical phenotype

Pulmonary arterial hypertension (PAH) is a severe disease characterised by progressive remodelling and loss of pulmonary microvessels, driven by endothelial cell dysfunction, smooth muscle cell abnormalities, inflammation and immune system dysregulation. Recent research advancements have uncovered pathogenic rare loss-of-function variants of SOX17 (SRY-box transcription factor 17) associated with PAH onset. SOX17, a member of the Sry-related high-mobility group box gene family, encodes a crucial transcription factor in embryogenesis, implicated in the formation and maintenance of endoderm, formation of the heart and vascular tree, and haematopoiesis and stem cell formation, with a strong relationship with hypoxia-inducible factors. Consistent with SOX17's pleiotropic embryogenic role, PAH patients carrying SOX17 variants present a particular phenotype associated with congenital heart diseases, younger age, as well as thoracic and extrathoracic vascular anomalies. Genetic and fundamental evidence suggest that SOX17 deficiency is a common occurrence in other forms of PAH. SOX17 deficiency appears to be central in PAH pathophysiology, playing a core role in endothelial dysfunction, intercellular crosstalk and endothelial-to-mesenchymal transition, with differential expression in males and females. Taken together, these data suggest its role as key element of the "multiple hits" theory of PAH, both as a first and second hit and support the notion that therapies aimed at restoring or enhancing its expression may offer promising therapeutic potential for all PAH patients. In this review, we integrate the latest knowledge on SOX17 function in embryogenesis and the PAH pathogenesis to provide an in-depth perspective on SOX17 function in cardiovascular and pulmonary physiology.