Endothelial Senescence Mediates Hypoxia-induced Vascular Remodeling in the Lung through TWIST1 Signaling

Pulmonary hypertension (PH) is a fatal pulmonary vascular disease characterized by a sustained elevation of pulmonary arterial (PA) pressure. The major characteristic of PH is uncontrolled accumulation of PA smooth muscle cells (SMCs) to normally non-muscularized distal PAs. Disrupted PA endothelial cell (EC) signaling stimulates PASMC proliferation and accumulation to distal PAs. Cellular senescence contributes to aging and lung diseases associated with PH. The mechanistic role of EC senescence in pathogenesis of PH has not been fully understood. We reported that a transcription factor, TWIST1 in ECs mediates hypoxia-induced accumulation of PASMCs to PAs by increasing platelet-derived growth factor (PDGFB) expression. Here we have demonstrated that the levels of senescence markers are higher in ECs isolated from PH patients compared to those from healthy individuals. The levels of PDGFB upregulated in PH patient-derived ECs are inhibited by knocking down p16 INK4A expression or treatment with senolytic reagent ABT-263. Hypoxia-induced accumulation of α-smooth muscle actin (αSMA)-positive cells to the PAs and TWIST1 expression are attenuated in p16 INK4Afl/fl -Cdh5(PAC)-Cre ERT2 mice after tamoxifen induction. Consistent with others’ report, reoxygenation after hypoxia exposure reverses the hypoxia-induced PA remodeling. The reversal effects are inhibited in p16 INK4Afl/fl -Cdh5(PAC)-Cre ERT2 mice. Hypoxia-induced increases in the expression of PDGFB decrease, while Apelin that inhibits PASMC proliferation increases after reoxygenation. These results suggest that EC senescence mediates vascular remodeling in PH through TWIST1 signaling and EC senescence is necessary for the reversal of hypoxia-induced PA remodeling. This project is supported by NIH R01HL139638 and AHA 967800. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.