C26-06 The Role of Senescent Pulmonary Artery Endothelial Cells in Pulmonary Hypertension Associated With Pulmonary Fibrosis

Rationale Pulmonary hypertension (PH) is a lethal complication of pulmonary fibrosis (PF). In PF lungs, cellular senescence of airway epithelial cells and fibroblasts has been reported to contribute to disease progression. However, the role of senescent vascular endothelial cells in PF and PF-associated PH remains poorly understood. In this study, we investigated the role of senescent vascular endothelial cells in fibrotic lungs. Methods To evaluate cellular senescence of vascular endothelial cells, immunofluorescence staining was performed on lungs from patients with PF and from an AdTGF-β1-induced rat model developing both PF and PH. To induce cellular senescence, human pulmonary artery endothelial cells (PAECs) were treated with TGF-β. Senescence induction was confirmed by SA-β-gal staining and p16/p21 expression. To investigate the paracrine effects of senescent PAECs on major structural components of the pulmonary artery, conditioned media (CM) were collected from senescent PAECs and applied to pulmonary artery smooth muscle cells (PASMCs) and fibroblasts. Following CM treatment, phenotypic changes in PASMCs and fibroblasts were evaluated by CCK-8 assay and western blotting. Results In lungs from PF patients, senescent endothelial cells were observed in pulmonary arteries. Similar findings were detected in lungs of the AdTGF-β1-induced rat model. In PAECs, TGF-β induced the expression of p16 and p21, increased IL-6 secretion, and enhanced SA-β-gal positivity and γH2A.X immunofluorescence. CM from TGF-β-induced senescent PAECs enhanced the proliferation of PASMCs and promoted extracellular matrix production in fibroblasts. TGF-β downregulated the expression of SOX17, an endothelium-specific transcription factor that promotes angiogenesis, in PAECs. Knockdown of SOX17 induced cellular senescence and activated the Notch signaling pathway in PAECs. Inhibition of Notch signaling attenuated SOX17 knockdown-induced cellular senescence in PAECs. In lungs from PF patients with PH and the AdTGF-β1-induced rat model, SOX17 expression was decreased in vascular endothelial cells. Conclusion Our findings demonstrate that vascular endothelial cell senescence occurs in PF-associated PH and contributes to pulmonary vascular remodeling through paracrine mechanisms involving the SOX17-Notch signaling axis. Targeting endothelial senescence may represent a novel therapeutic strategy for preventing or treating PH in patients with PF. This abstract is funded by: None