E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension

Area of Science:

• Cardiovascular Biology
• Pulmonary Hypertension Pathogenesis
• Genetic Regulation of Vascular Cells

Background:

• Genetic variants in SOX17 are linked to idiopathic pulmonary arterial hypertension (PAH), but its role in disease development is unclear.
• Pulmonary hypertension (PH) involves complex genetic and cellular mechanisms requiring further investigation.

Approach:

• Assessed SOX17 expression in human IPAH lung tissue and endothelial cells (ECs).
• Utilized genetically modified mice with SOX17 deficiency in ECs to model PH development.
• Employed single-cell RNA sequencing and cell culture to elucidate SOX17's molecular mechanisms.

Key Points:

• SOX17 expression is reduced in IPAH lungs and ECs.
• Endothelial SOX17 deficiency in mice leads to PH and exacerbates hypoxia-induced PH.
• SOX17 loss impairs EC function, promoting proliferation, anti-apoptosis, and altered cell-cell junctions, mediated by E2F1 signaling.

Conclusions:

• Endothelial SOX17 deficiency is a driver of PH pathogenesis.
• E2F1 signaling is a key mediator of SOX17 deficiency-induced EC dysfunction and PH.
• Targeting E2F1 represents a potential therapeutic avenue for PAH treatment.