Cargando…

Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells

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 t...

Descripción completa

Detalles Bibliográficos
Autores principales: Sun, Yifei, Asano, Keiichi, Sedes, Lauriane, Cantalupo, Anna, Hansen, Jens, Iyengar, Ravi, Walsh, Martin J., Ramirez, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322683/
https://www.ncbi.nlm.nih.gov/pubmed/37022786
http://dx.doi.org/10.1172/jci.insight.168793
_version_ 1785068812141330432
author Sun, Yifei
Asano, Keiichi
Sedes, Lauriane
Cantalupo, Anna
Hansen, Jens
Iyengar, Ravi
Walsh, Martin J.
Ramirez, Francesco
author_facet Sun, Yifei
Asano, Keiichi
Sedes, Lauriane
Cantalupo, Anna
Hansen, Jens
Iyengar, Ravi
Walsh, Martin J.
Ramirez, Francesco
author_sort Sun, Yifei
collection PubMed
description 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 Fbn1(mgR/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 Fbn1(mgR/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 Fbn1(mgR/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.
format Online
Article
Text
id pubmed-10322683
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher American Society for Clinical Investigation
record_format MEDLINE/PubMed
spelling pubmed-103226832023-07-07 Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells Sun, Yifei Asano, Keiichi Sedes, Lauriane Cantalupo, Anna Hansen, Jens Iyengar, Ravi Walsh, Martin J. Ramirez, Francesco JCI Insight Research Article 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 Fbn1(mgR/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 Fbn1(mgR/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 Fbn1(mgR/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. American Society for Clinical Investigation 2023-05-22 /pmc/articles/PMC10322683/ /pubmed/37022786 http://dx.doi.org/10.1172/jci.insight.168793 Text en © 2023 Sun et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Sun, Yifei
Asano, Keiichi
Sedes, Lauriane
Cantalupo, Anna
Hansen, Jens
Iyengar, Ravi
Walsh, Martin J.
Ramirez, Francesco
Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells
title Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells
title_full Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells
title_fullStr Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells
title_full_unstemmed Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells
title_short Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells
title_sort dissecting aortic aneurysm in marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322683/
https://www.ncbi.nlm.nih.gov/pubmed/37022786
http://dx.doi.org/10.1172/jci.insight.168793
work_keys_str_mv AT sunyifei dissectingaorticaneurysminmarfansyndromeisassociatedwithlosartansensitivetranscriptomicmodulationofaorticcells
AT asanokeiichi dissectingaorticaneurysminmarfansyndromeisassociatedwithlosartansensitivetranscriptomicmodulationofaorticcells
AT sedeslauriane dissectingaorticaneurysminmarfansyndromeisassociatedwithlosartansensitivetranscriptomicmodulationofaorticcells
AT cantalupoanna dissectingaorticaneurysminmarfansyndromeisassociatedwithlosartansensitivetranscriptomicmodulationofaorticcells
AT hansenjens dissectingaorticaneurysminmarfansyndromeisassociatedwithlosartansensitivetranscriptomicmodulationofaorticcells
AT iyengarravi dissectingaorticaneurysminmarfansyndromeisassociatedwithlosartansensitivetranscriptomicmodulationofaorticcells
AT walshmartinj dissectingaorticaneurysminmarfansyndromeisassociatedwithlosartansensitivetranscriptomicmodulationofaorticcells
AT ramirezfrancesco dissectingaorticaneurysminmarfansyndromeisassociatedwithlosartansensitivetranscriptomicmodulationofaorticcells