E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension.

Area of Science:

• Cardiovascular Research
• Pulmonary Medicine
• Genetics

Background:

• Rare genetic variants in SOX17 (SRY-box transcription factor 17) are linked to idiopathic pulmonary arterial hypertension (PAH).
• The precise role of SOX17 genetic variations in PAH pathogenesis remains unclear.

Purpose of the Study:

• To investigate the role of SOX17 in pulmonary arterial hypertension (PAH).
• To elucidate the molecular mechanisms by which SOX17 deficiency contributes to PAH.

Main Methods:

• Evaluated SOX17 expression in human idiopathic PAH lungs and pulmonary endothelial cells (ECs).
• Generated mice with EC-specific Sox17 deletion to study PAH pathogenesis.
• Utilized single-cell RNA sequencing and RNA-sequencing analysis.
• Investigated the role of E2F1 (E2F transcription factor 1) signaling and tested an E2F1 inhibitor.

Main Results:

• SOX17 expression was significantly downregulated in idiopathic PAH lungs and pulmonary ECs.
• EC-specific Sox17 deletion in mice induced mild pulmonary hypertension and exacerbated hypoxia-induced PAH.
• SOX17 loss in ECs led to endothelial dysfunction, including altered cell cycle, proliferation, apoptosis, paracrine signaling, and impaired BMP signaling.
• E2F1 signaling mediated SOX17 deficiency-induced EC dysfunction, and its inhibition attenuated PAH development in mice.

Conclusions:

• Endothelial SOX17 deficiency is a key driver of pulmonary hypertension through E2F1 signaling.
• Targeting E2F1 signaling presents a promising therapeutic avenue for patients with pulmonary arterial hypertension (PAH).