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| Status |
Public on Apr 30, 2023 |
| Title |
Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we show that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice that we recently generated, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice exposed to chronic hypoxia. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions in vitro, and improved the worsened pulmonary hypertension in EC-specific progeroid mice in vivo. Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly.
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| Overall design |
single nucleus RNA sequencing was used to profile mouse lung
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| Contributor(s) |
Ikeda K |
| Citation missing |
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| Submission date |
Mar 29, 2023 |
| Last update date |
May 02, 2023 |
| Contact name |
Tetsuro Kusaba |
| Organization name |
Graduate School of Medical Science, Kyoto Prefectural University of Medicine
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| Department |
Department of Nephrology
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| Street address |
465 Kajii-cho, Kamigyo-ku
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| City |
Kyoto |
| State/province |
Kyoto |
| ZIP/Postal code |
6028566 |
| Country |
Japan |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA950045 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE228491_RAW.tar |
1.4 Gb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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