E2F1 Drives Endothelial Arterial Programming in Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is driven by maladaptive endothelial remodeling, but the transcriptional regulators that couple proliferative stress to arterialized endothelial states remain incompletely defined. E2F transcription factor 1 (E2F1) is classically viewed as a cell-cycle regulator; whether E2F1 functions as a disease-driving node that promotes endothelial arterial programming in PAH remains unknown. Methods: We integrated human PAH lung transcriptomic analyses, deconvolution-based endothelial-state scoring, and complementary mouse and rat PH models with bulk RNA-seq, single-cell RNA-seq, pseudotime analysis, and CellChat inference. E2F1 function was tested using adenoviral E2F1 overexpression, pharmacological pan-E2F inhibition with HLM006474, and genetic Results: In PAH lungs, E2F1 was increased and arterial endothelial cell (AEC) fraction and expanded arterial program scores were elevated. Similarly, Conclusions: E2F1 acts as a disease-relevant transcriptional factor linking endothelial cell-cycle activation to arterial programming, matrix and angiogenic communication programs, and pulmonary vascular remodeling. Genetic or pharmacological E2F inhibition mitigates experimental PH, supporting E2F1 as a therapeutic target in PAH.