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

Abstract

Pulmonary hypertension (PH) is a fatal pulmonary vascular disease characterized by a sustained elevation of pulmonary arterial pressure. One of the major characteristics of PH is uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMCs) to normally non‐muscularized distal pulmonary arteries (PAs). Cellular senescence contributes to aging and lung diseases associated with PH. The aim of this study is to understand the mechanism by which cellular senescence controls vascular remodeling in PH. We have reported that a basic helix‐loop‐helix transcription factor, TWIST1, in endothelial cells (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, p16INK4A and senescence‐associated β‐galactosidase (SA‐β‐gal) are higher in ECs isolated from PH patients compared to those from healthy individuals. Analysis of publicly available RNAseq data of PH patient lungs reveals the interaction between TWIST1 and senescence‐related genes. The levels of PDGFB upregulated in PH patient‐derived ECs are inhibited by knocking down p16INK4A expression or treatment with senolytic reagent ABT‐263. Hypoxia‐induced accumulation of a‐smooth muscle actin (aSMA)‐positive cells to the PAs and TWIST1 expression are attenuated in p16INK4Afl/fl‐Cdh5(PAC)‐CreERT2 mice after tamoxifen induction. These results suggest that EC senescence mediates vascular remodeling in PH through TWIST1 signaling.