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| Status |
Public on Dec 29, 2023 |
| Title |
Endothelial cells drive organ fibrosis and dysfunction by inducing the transcription factor SOX9 (ATAC-Seq) |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Fibrosis is a hallmark of chronic disease. Although fibroblasts are known to be involved, it is unclear to what extent endothelial cells might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells of fibrotic mouse organs in models of systolic heart failure by pressure overload, diastolic heart failure by high-fat diet and L-Name administration, pulmonary fibrosis after bleomycin treatment, and liver fibrosis as consequence of CDAA diet. We also observed endothelial SOX9 upregulation in human heart tissue in patients with heart failure. To test whether this SOX9 induction was sufficient to cause disease, we generated mice with endothelial cell-specific overexpression of Sox9, which indeed triggered extensive fibrosis in multiple organs and promoted signs of heart failure. Endothelial Sox9 deletion, in turn, prevented fibrosis and organ dysfunction in pre-clinical surgical and pharmacological mouse models of heart failure as well as of lung, and liver injury. Bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that SOX9 induced extracellular matrix, growth factor, and inflammatory genes leading to matrix deposition by endothelial cells. Moreover, in part through triggering an increased expression of the secreted growth factor Ccn2 as direct SOX9 target, endothelial cells activated neighboring fibroblasts to migrate and deposit matrix in response to SOX9. Endothelial Sox9 deletion reversed these changes, suggesting a role for endothelial SOX9 as fibrosis-promoting transcription factor across organs in response to disease stimuli. Therefore, endothelial cells could be a promising target to counteract fibrotic heart, liver and lung disease
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| Overall design |
ATAC-seq was performed in cardiac EC from Ctr and Sox9_OE induced mice after 1 month of tamoxifen treatment.
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| Contributor(s) |
Trogisch FA, Cordero J, Elsherbiny A, Keles M, Heineke J |
| Citation(s) |
38416842 |
| Submission date |
Dec 26, 2023 |
| Last update date |
Mar 05, 2024 |
| Contact name |
Joerg Heineke |
| E-mail(s) |
Joerg.Heineke@medma.uni-heidelberg.de
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| Organization name |
Medizinische Fakultät Mannheim
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| Department |
– Department of Cardiovascular Research (HKF)
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| Street address |
Ludolf-Krehl-Str. 7-11
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| City |
Mannheim |
| State/province |
Baden Wuttemberg |
| ZIP/Postal code |
68167 |
| Country |
Germany |
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| Platforms (1) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE198041 |
Vascular endothelial cells drive organ fibrosis by inducing the transcription factor Sox9 |
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| Relations |
| BioProject |
PRJNA1057301 |
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