The aim of this study was to outline spatial and temporal dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS).
Single-cell RNA sequencing was conducted in order to study ascending/aortic root aneurysm tissue from healthy controls and Fbn1C1041G/+ (MFS) mice, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1C1041G/+ 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 (Serpine1) and Kruppel-like factor 4 (Klf4). Pseudotime trajectory analysis of Fbn1C1041G/+ SMC/modSMC transcriptomes identified genes activated differentially throughout phenotype modulation. While modSMCs were not present in young Fbn1C1041G/+ mouse aortas despite a small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1C1041G/+ descending thoracic aortas.
In conclusion, dynamic SMC phenotype modulation promotes aortic aneurysm progression and extracellular matrix substrate modulation in MFS. The disease-specific signature of modSMCs was characterized. Along with the provision of temporal, transcriptomic context to the current understanding of the role TGF-β plays in MFS aortopathy. Single-cell RNA sequencing implies that Klf4 overexpression and TGF-β signaling as prospective drivers of SMC modulation.
Ref: https://www.ahajournals.org/doi/10.1161/ATVBAHA.120.314670
