Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells.
JCI Insight
; 8(10)2023 05 22.
Article
em En
| MEDLINE
| ID: mdl-37022786
ABSTRACT
To improve our limited understanding of the pathogenesis of thoracic aortic aneurysm (TAA) that leads to acute aortic dissection, single-cell RNA sequencing (scRNA-seq) was employed to profile disease-relevant transcriptomic changes of aortic cell populations in a well-characterized mouse model of the most commonly diagnosed form of Marfan syndrome (MFS). As result, 2 discrete subpopulations of aortic cells (SMC3 and EC4) were identified only in the aorta of Fbn1mgR/mgR mice. SMC3 cells highly express genes related to extracellular matrix formation and nitric oxide signaling, whereas the EC4 transcriptional profile is enriched in smooth muscle cell (SMC), fibroblast, and immune cell-related genes. Trajectory analysis predicted close phenotypic modulation between SMC3 and EC4, which were therefore analyzed together as a discrete MFS-modulated (MFSmod) subpopulation. In situ hybridization of diagnostic transcripts located MFSmod cells at the intima of Fbn1mgR/mgR aortas. Reference-based data set integration revealed transcriptomic similarity between MFSmod- and SMC-derived cell clusters modulated in human TAA. Consistent with the angiotensin II type I receptor (At1r) contribution to TAA development, MFSmod cells were absent in the aorta of Fbn1mgR/mgR mice treated with the At1r antagonist losartan. Altogether, our findings indicate that a discrete dynamic alteration of aortic cell identity is associated with dissecting TAA in MFS mice and increased risk of aortic dissection in MFS patients.
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Base de dados:
MEDLINE
Assunto principal:
Aneurisma Aórtico
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Aneurisma da Aorta Torácica
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Dissecção Aórtica
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Síndrome de Marfan
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article