E2F1 Drives Endothelial Arterial Programming in Pulmonary Arterial Hypertension

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Transcriptional Regulation

Background:

• Pulmonary arterial hypertension (PAH) involves endothelial remodeling, but regulators linking proliferation to arterial states are unclear.
• E2F transcription factor 1 (E2F1), a cell-cycle regulator, is investigated for its role in PAH-associated endothelial arterial programming.

Purpose of the Study:

• To investigate the role of E2F transcription factor 1 (E2F1) in pulmonary arterial hypertension (PAH).
• To determine if E2F1 acts as a disease-driving node promoting endothelial arterial programming in PAH.
• To evaluate E2F1 inhibition as a potential therapeutic strategy for PAH.

Main Methods:

• Integrated human PAH transcriptomics, mouse/rat PH models, bulk and single-cell RNA-seq, and CellChat analysis.
• Tested E2F1 function via overexpression, pharmacological inhibition (HLM006474), and genetic loss in mouse models.
• Utilized adenoviral vectors, specific genetic deletions (E2f1, Egln1), and tamoxifen-inducible systems.

Main Results:

• E2F1 was elevated in PAH lungs, correlating with increased arterial endothelial cell fraction and arterial program scores.
• Genetic loss of E2F1 reduced PH severity, vascular remodeling, and right ventricle hypertrophy in mouse models.
• E2F1 inhibition suppressed endothelial proliferation and attenuated experimental PH, with established PH reversal observed.

Conclusions:

• E2F1 functions as a key transcriptional factor linking endothelial cell-cycle activation to arterial programming and vascular remodeling in PAH.
• Genetic or pharmacological inhibition of E2F1 effectively mitigates experimental PH.
• E2F1 represents a promising therapeutic target for treating pulmonary arterial hypertension.