Introduction: Pulmonary hypertension (PH) is a common complication of advanced idiopathic pulmonary fibrosis (IPF). Pulmonary endothelial dysfunction is a defining feature of vascular remodeling in pulmonary arterial hypertension, but it is less well-defined across PH subtypes. Cellular senescence is an evolutionarily conserved state of stable replicative arrest induced by pro-aging stressors and is implicated in epithelial cells and fibroblasts in IPF lungs. However, the involvement of endothelial cellular senescence in IPF is still unclear. We investigated the role of endothelial cellular senescence in the pathogenesis of IPF with PH using human lung and animal model.

Methods: Lung tissue from healthy subjects and IPF patients was used to evaluate senescence markers. Adult Sprague-Dawley rats were treated with an adenoviral vector encoding active TGF-?1 (AdTGF-?1). PAEC and HUVEC were used for in vitro experiments.

Results: In the lungs of IPF patients, increased expression of senescence markers was observed in endothelial cells as well as epithelial cells. Furthermore, in the lungs of IPF complicated with PH, expression of Sox17 was decreased. In the rat model of AdTGF-?1-induced pulmonary fibrosis with PH, increased senescence markers and decreased Sox17 expression were observed in lung endothelial cells. In vitro experiments showed that TGF-?1 stimulation and Sox17 knockdown induce endothelial cellular senescence.

Conclusions: These findings suggest that TGF-?1-induced lung endothelial cellular senescence is a key process of vascular remodeling in group 3 PH and that Sox17-regulated endothelial cellular senescence is involved in PH development in IPF patients.