Aortic & peripheral vascular disease
Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections
Authors' conclusion
Our study reveals the dynamic epigenetic induction of SMC phenotypic alterations in AAD. DNA damage and cytosolic leakage drive SMCs from a contractile phenotype to an inflammatory phenotype.
Study context
- Population
- Mice with angiotensin II-induced aortic aneurysm and dissection (AAD); aortas from patients with ascending thoracic AAD
- Outcome
- SMC phenotypic alterations in AAD
Methodological detailssingle-cell RNA sequencing, single-cell ATAC sequencing, lineage tracing
- Single-cell RNA sequencing
- Single-cell ATAC sequencing
- Lineage tracing
Main finding
As reported in the abstract
- Aortic stress induced smooth muscle cell (SMC) transition from contractile to proliferative, ECM-producing and inflammatory phenotypes
- Lineage tracing: complete transformation of SMCs to fibroblasts and macrophages
- Phenotypic alterations controlled by chromatin remodelling: reduced accessibility of contractile genes, induced accessibility of proliferation, ECM and inflammation genes
- IRF3 identified as key driver of contractile-to-inflammatory SMC transition
- In cultured SMCs, cytosolic DNA–STING–TBK1 activated IRF3, which recruited EZH2 to contractile genes, inducing H3K27me3 and gene suppression; dsDNA-STING-IRF3 signalling induced inflammatory gene expression
- In Sting-/- mice, stress-induced transition to inflammatory phenotype prevented and SMC populations preserved
- Profound SMC phenotypic alterations toward diverse directions in human ascending thoracic AAD tissues
Original publication
Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections. Circulation. Published 9 August 2023. doi:10.
Summarised from the published abstract; every number is checked against it