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. 2024 Nov;44(11):e264-e276.

doi: 10.1161/ATVBAHA.123.320330. Epub 2024 Sep 5.

Spatial Transcriptomic Approach to Understanding Coronary Atherosclerotic Plaque Stability

Maria G Gastanadui^{1

2}, Camilla Margaroli^{3

4}, Silvio Litovsky^{5

6}, Robert P Richter^{4

7}, Dezhi Wang⁸, Dongqi Xing^{2

4

9

10

11}, J Michael Wells^{2

4

9

10

11

12}, Amit Gaggar^{2

4

9

10

11

13

12}, Vivek Nanda³, Rakesh P Patel^{2

3

4

14}, Gregory A Payne^{1

2

4

6

11

12}

Affiliations

Affiliations

¹ Department of Medicine, Division of Cardiovascular Disease (M.G.G., G.A.P.), University of Alabama at Birmingham.
² Cardiopulmonary Research Program, Department of Medicine (M.G.G., D.X., J.M.W., A.G., R.P.P., G.A.P.), University of Alabama at Birmingham.
³ Department of Pathology, Division of Molecular and Cellular Pathology (C.M., V.N., R.P.P.), University of Alabama at Birmingham.
⁴ Program in Protease/Matrix Biology (C.M., R.P.R., D.X., J.M.W., A.G., R.P.P., G.A.P.), University of Alabama at Birmingham.
⁵ Department of Pathology, Division of Anatomic Pathology (S.L.), University of Alabama at Birmingham.
⁶ Comprehensive Cardiovascular Center (S.L., G.A.P.), University of Alabama at Birmingham.
⁷ Department of Pediatrics, Division of Pediatric Critical Care (R.P.R.), University of Alabama at Birmingham.
⁸ Department of Pathology, Pathology Core Research Laboratory (D.W.), University of Alabama at Birmingham.
⁹ Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (D.X., J.M.W., A.G.), University of Alabama at Birmingham.
¹⁰ Lung Health Center (D.X., J.M.W., A.G.), University of Alabama at Birmingham.
¹¹ Vascular Biology and Hypertension Program (G.A.P., D.X., J.M.W., A.G.), University of Alabama at Birmingham.
¹² Medical Service at Birmingham VA Medical Center, AL (J.M.W., G.A.P., A.G.).
¹³ Department of Cell, Developmental, and Integrative Biology (A.G., A.G.), University of Alabama at Birmingham.
¹⁴ Center for Free Radical Biology (R.P.P.), University of Alabama at Birmingham.

PMID: 39234691
PMCID: PMC11499036 (available on 2025-11-01)
DOI: 10.1161/ATVBAHA.123.320330

Spatial Transcriptomic Approach to Understanding Coronary Atherosclerotic Plaque Stability

Maria G Gastanadui et al. Arterioscler Thromb Vasc Biol. 2024 Nov.

. 2024 Nov;44(11):e264-e276.

doi: 10.1161/ATVBAHA.123.320330. Epub 2024 Sep 5.

Authors

Maria G Gastanadui^{1

2}, Camilla Margaroli^{3

4}, Silvio Litovsky^{5

6}, Robert P Richter^{4

7}, Dezhi Wang⁸, Dongqi Xing^{2

4

9

10

11}, J Michael Wells^{2

4

9

10

11

12}, Amit Gaggar^{2

4

9

10

11

13

12}, Vivek Nanda³, Rakesh P Patel^{2

3

4

14}, Gregory A Payne^{1

2

4

6

11

12}

Affiliations

¹ Department of Medicine, Division of Cardiovascular Disease (M.G.G., G.A.P.), University of Alabama at Birmingham.
² Cardiopulmonary Research Program, Department of Medicine (M.G.G., D.X., J.M.W., A.G., R.P.P., G.A.P.), University of Alabama at Birmingham.
³ Department of Pathology, Division of Molecular and Cellular Pathology (C.M., V.N., R.P.P.), University of Alabama at Birmingham.
⁴ Program in Protease/Matrix Biology (C.M., R.P.R., D.X., J.M.W., A.G., R.P.P., G.A.P.), University of Alabama at Birmingham.
⁵ Department of Pathology, Division of Anatomic Pathology (S.L.), University of Alabama at Birmingham.
⁶ Comprehensive Cardiovascular Center (S.L., G.A.P.), University of Alabama at Birmingham.
⁷ Department of Pediatrics, Division of Pediatric Critical Care (R.P.R.), University of Alabama at Birmingham.
⁸ Department of Pathology, Pathology Core Research Laboratory (D.W.), University of Alabama at Birmingham.
⁹ Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (D.X., J.M.W., A.G.), University of Alabama at Birmingham.
¹⁰ Lung Health Center (D.X., J.M.W., A.G.), University of Alabama at Birmingham.
¹¹ Vascular Biology and Hypertension Program (G.A.P., D.X., J.M.W., A.G.), University of Alabama at Birmingham.
¹² Medical Service at Birmingham VA Medical Center, AL (J.M.W., G.A.P., A.G.).
¹³ Department of Cell, Developmental, and Integrative Biology (A.G., A.G.), University of Alabama at Birmingham.
¹⁴ Center for Free Radical Biology (R.P.P.), University of Alabama at Birmingham.

PMID: 39234691
PMCID: PMC11499036 (available on 2025-11-01)
DOI: 10.1161/ATVBAHA.123.320330

Abstract

Background: Coronary atherosclerotic plaques susceptible to acute coronary syndrome have traditionally been characterized by their surrounding cellular architecture. However, with the advent of intravascular imaging, novel mechanisms of coronary thrombosis have emerged, challenging our contemporary understanding of acute coronary syndrome. These intriguing findings underscore the necessity for a precise molecular definition of plaque stability. Considering this, our study aimed to investigate the vascular microenvironment in patients with stable and unstable plaques using spatial transcriptomics.

Methods: Autopsy-derived coronary arteries were preserved and categorized by plaque stability (n=5 patients per group). We utilized the GeoMx spatial profiling platform and Whole Transcriptome Atlas to link crucial histological morphology markers in coronary lesions with differential gene expression in specific regions of interest, thereby mapping the vascular transcriptome. This innovative approach allowed us to conduct cell morphological and spatially resolved transcriptional profiling of atherosclerotic plaques while preserving crucial intercellular signaling.

Results: We observed intriguing spatial and cell-specific transcriptional patterns in stable and unstable atherosclerotic plaques, showcasing regional variations within the intima and media. These regions exhibited differential expression of proinflammatory molecules (eg, IFN-γ [interferon-γ], MHC [major histocompatibility complex] class II, proinflammatory cytokines) and prothrombotic signaling pathways. By using lineage tracing through spatial deconvolution of intimal CD68⁺ (cluster of differentiation 68) cells, we characterized unique, intraplaque subpopulations originating from endothelial, smooth muscle, and myeloid lineages with distinct regional locations associated with plaque instability. In addition, unique transcriptional signatures were observed in vascular smooth muscle and CD68⁺ cells among plaques exhibiting coronary calcification.

Conclusions: Our study illuminates distinct cell-specific and regional transcriptional alterations present in unstable plaques. Furthermore, we characterize spatially resolved, in situ evidence supporting cellular transdifferentiation and intraplaque plasticity as significant contributors to plaque instability in human coronary atherosclerosis. Our results provide a powerful resource for the identification of novel mediators of acute coronary syndrome, opening new avenues for preventative and therapeutic treatments.

Keywords: acute coronary syndrome; atherosclerosis; coronary thrombosis; macrophages; muscle, smooth, vascular.

PubMed Disclaimer

Conflict of interest statement

None.

Comment in

Spatial Transcriptomics: A New Frontier in Atherosclerosis Research?
Cole JE, Monaco C. Cole JE, et al. Arterioscler Thromb Vasc Biol. 2024 Nov;44(11):2291-2293. doi: 10.1161/ATVBAHA.124.321652. Epub 2024 Oct 23. Arterioscler Thromb Vasc Biol. 2024. PMID: 39441914 No abstract available.

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