Abstract
Abstract 4368540: A Spatially Resolved Transcriptomic Signature of Atherosclerotic Plaque Stabilization and Regression
Circulation (New York, N.Y.), Vol.152(Suppl_3), pp.A4368540-A4368540
11/04/2025
DOI: 10.1161/circ.152.suppl_3.4368540
Abstract
Introduction: Major adverse cardiovascular events (MACE) in those with atherosclerotic cardiovascular disease (ASCVD) continues to be a leading contributor to death worldwide, driven by rising rates of cardiometabolic diseases such as Type 2 Diabetes Mellitus and Hyperlipidemia. MACE remain prevalent despite guideline-directed use of medications to treat cardiometabolic disease in those with ASCVD. This suggests that mechanisms of disease persist, even after "normalization" of risk factor markers.
Question: What pathways and transcriptomic patterns are associated with the regression of atherosclerotic plaques in mice?
Methods: Reversa mice with or without treatment with a pro-resolving mediator of inflammation (Ac2-26) were used as a model of plaque progression, stabilization, and regression. "Standard definition" Visium spatial transcriptomics was performed on reliably plaque bearing aortic root sections. Transcriptomic spatial barcodes were aligned with imaging of hematoxylin and eosin staining of the same section using Space Ranger before manual binning of cell types and subsequent pairwise comparisons in 10x' Loupe Browser between cell-types, including endothelial cells, vascular smooth muscle cells of the annulus, and neointima in four cohorts: wild-type (WT), Reversa (high cholesterol), Reversed Reversa (high cholesterol diet followed by pI-pC induced knockdown), and a Reversed Reversa group exposed to Ac2-26.
Results: WT mice do not develop aortic plaques. Reversa mice show neointimal development in the aortic root while the Reversed Reversa with and without Ac2-26 mice show plaque compositional changes and size reductions. Spatial transcriptomics of aortic root slices revealed Myl9, Tpm2, Acta2, and Igfbp7 as downregulated in Reversa and Reveresed Reversa mice, compared to WT, but not in those treated with Ac2-26
Conclusion: We have identified transcripts whose differential expression is strongly associated with the regression of plaques but not stabilization, indicating that these transcripts may represent a signature of healthy vasculature that are not corrected by lowering cholesterol. Future studies will investigate whether Ac2-26 can induce plaque regression in the absence of cholesterol lowering and whether targeting of 'healthy' genes identified in this study can accelerate plaque regression in mice. We aim to apply findings of this study in the pursuit of mechanisms that may promote return of vascular health and reduce MACE in those with ASCVD.
Details
- Title: Subtitle
- Abstract 4368540: A Spatially Resolved Transcriptomic Signature of Atherosclerotic Plaque Stabilization and Regression
- Creators
- Luis Persaud - University of IowaLi-Hsien Lin - University of IowaRobert Weiss - University of IowaWilliam Kutschke - University of IowaJennifer Streeter - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.152(Suppl_3), pp.A4368540-A4368540
- DOI
- 10.1161/circ.152.suppl_3.4368540
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Publisher
- Lippincott Williams & Wilkins
- Language
- English
- Date published
- 11/04/2025
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9985021952502771
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