Arteriosclerosis, thrombosis, and vascular biology, 2020-09, Vol.40 (9), p.2195-2211
2020
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- Autor(en) / Beteiligte
- Titel
- Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm
- Ist Teil von
- Arteriosclerosis, thrombosis, and vascular biology, 2020-09, Vol.40 (9), p.2195-2211
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 ( ) and Kruppel-like factor 4 ( ). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF-β (transforming growth factor beta)-responsive genes correlated with SMC modulation in mouse and human data sets. Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-β plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-β signaling and overexpression as potential upstream drivers of SMC modulation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1079-5642eISSN: 1524-4636DOI: 10.1161/ATVBAHA.120.314670Titel-ID: cdi_pubmed_primary_32698686
- Format
- –
- Schlagworte
- Animals, Aorta - metabolism, Aorta - pathology, Aortic Aneurysm - genetics, Aortic Aneurysm - metabolism, Aortic Aneurysm - pathology, Atherosclerosis - genetics, Atherosclerosis - metabolism, Atherosclerosis - pathology, Disease Models, Animal, Disease Progression, Extracellular Matrix - genetics, Extracellular Matrix - metabolism, Extracellular Matrix - pathology, Female, Fibrillin-1 - genetics, Gene Expression Profiling, Genetic Predisposition to Disease, Kruppel-Like Factor 4, Male, Marfan Syndrome - complications, Marfan Syndrome - genetics, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Smooth, Vascular - metabolism, Muscle, Smooth, Vascular - pathology, Mutation, Myocytes, Smooth Muscle - metabolism, Myocytes, Smooth Muscle - pathology, Phenotype, RNA-Seq, Single-Cell Analysis, Time Factors, Transcriptome, Vascular Remodeling - genetics