Abstract 4363001: Role of E2F Transcription Factor 1 in the Pathogenesis of Pulmonary Arterial Hypertension

Background: Dysregulated expression of transcription factors plays a key role in vascular remodeling and the development of pulmonary arterial hypertension (PAH). E2F1 is a central regulator of the cell cycle, apoptosis, and DNA damage response; however, its role in vascular remodeling and PAH remains poorly understood. Hypothesis: Upregulation of E2F1 contributes to pulmonary vascular remodeling and the pathogenesis of PAH. Approach: E2F1 expression was evaluated in pulmonary endothelial cells (ECs) from idiopathic PAH (IPAH) patients compared to healthy donors, and in whole-lung tissues from wild-type (WT) and Egln1Tie2Cre mice (a severe PH model), as well as monocrotaline (MCT)-exposed PH rats using bulk RNA sequencing, qPCR, and Western blot. To assess endothelial dysfunction, E2F1 was overexpressed in human lung ECs via adenoviral delivery. To investigate the in vivo role of E2F1, we generated E2f1 knockout mice ( E2f1-/-;Egln1Cdh5CreERT2 , referred to as iDKO) by crossing E2f1-/- mice with Egln1Cdh5CreERT2 mice (iCKO). Hemodynamic and morphological parameters were compared between iDKO and iCKO mice. Bulk RNA-seq was performed to identify E2F1-regulated pathways. Additionally, a pharmacological E2F1 inhibitor was administered to MCT-treated rats to evaluate therapeutic potential. Results: E2F1 expression was significantly elevated in pulmonary ECs of IPAH patients compared to healthy controls. Similarly, E2F1 levels were markedly increased in Egln1Tie2Cre mice and MCT-induced PH rats. Deletion of E2F1 (iDKO) led to significant reductions in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RV/LV+S ratio) compared to iCKO mice. Bulk RNA-seq analysis revealed enrichment of E2F1-associated pathways contributing to PH. Notably, pharmacological inhibition of E2F1 attenuated PH development in MCT rats. Conclusion: Our findings suggest that E2F1 upregulation promotes pulmonary vascular remodeling and PH development. Targeting E2F1 may represent a novel therapeutic strategy for mitigating vascular remodeling in PAH. Keywords: E2F1, endothelial dysfunction, vascular remodeling, pulmonary arterial hypertension (PAH)