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Endothelial Senescence Mediates Hypoxia‐induced Vascular Remodeling in the Lung through TWIST1 Signaling
Author(s) -
Kyi Priscilla,
Hunyenyiwa Tendai,
Hendee Kathryn,
Matus Kienna,
Mammoto Tadanori,
Mammoto Akiko
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r3904
Subject(s) - senescence , hypoxia (environmental) , pulmonary hypertension , vascular smooth muscle , lung , transcription factor , downregulation and upregulation , pulmonary artery , pdgfb , cancer research , microbiology and biotechnology , medicine , endocrinology , biology , chemistry , growth factor , biochemistry , platelet derived growth factor receptor , receptor , organic chemistry , smooth muscle , oxygen , gene
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, p16 INK4A 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 p16 INK4A 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 p16 INK4Afl/fl ‐Cdh5(PAC)‐Cre ERT2 mice after tamoxifen induction. These results suggest that EC senescence mediates vascular remodeling in PH through TWIST1 signaling.