In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
Abstract:
Introduction: Animal models are widely used to study pulmonary hypertension and test experimental therapies. The detailed cellular phenotypes of these diverse models, and their relationship to human disease remain unclear. Hypothesis: This study aimed to assess several commonly used models and their correlations with human disease at single-cell resolution. Methods: Single-cell RNA sequencing was performed on lung tissues from mice exposed to chronic hypoxia or SU5416 with hypoxia, rats exposed to monocrotaline, and control animals. Immunofluorescence was used to validate the findings in animal and patient tissues. Results: Perturbed cell populations in diseased rats and mice were similar to those in patients, with macrophages and endothelial cells being primarily affected. A novel DHCR24 high macrophage population harboring tissue remodeling and pro-inflammatory features were consistently increased across rodent models, and whose phenotypic modulation corresponded with disease progression. Functionally diverse endothelial subtypes were found, including a novel ETB + endothelial population with potentially protective functions. These endothelial subtypes exhibited key motifs of pulmonary hypertension, including enhanced apoptosis, dysregulated angiogenesis, proliferation, and reactive oxygen species-mediated stress. These macrophage and endothelial subtypes exhibited dysregulation of numerous genes targeted by approved PAH drugs. Changes in these cell populations were confirmed by animal and patient lung histology. Potential intercellular interactions between macrophage and endothelial subtypes, via ANGPTL4, CXCL12, or SEMA3 signaling, and autocrine endothelial signaling were predicted to occur. Conclusions: We established a comprehensive single-cell atlas of the mainstream rodent pulmonary hypertension models, and highlighted potential functional roles of novel macrophage and endothelial subpopulations.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.146.suppl_1.13237
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2022
detail.hit.zdb_id:
1466401-X
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