Evidence map›Paper›PMID 40120433›Full record

ArticleAtherosclerosis2025

Integrative analysis of single-cell transcriptomics and genetic associations identify cell states associated with vascular disease.

Mark E Pepin, William E Schwartzman, Shi Fang, Shamsudheen K Vellarikkal, Deepak S Atri, Ankith Reddy, Qiaohan Xu, Andrew R Hamel, Marie Billaud, Ayellet V Segrè and 1 more

Abstract read
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In one paragraph

Article in Atherosclerosis, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Mark E PepinThe Broad Institute of Harvard and MIT, Cambridge, MA, USA; Divisions of Genetics and Cardiovascular Medicine, Brigham & Women's Hospital, Boston, MA, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
William E SchwartzmanThe Broad Institute of Harvard and MIT, Cambridge, MA, USA; Divisions of Genetics and Cardiovascular Medicine, Brigham & Women's Hospital, Boston, MA, USA.
Shi FangThe Broad Institute of Harvard and MIT, Cambridge, MA, USA; Divisions of Genetics and Cardiovascular Medicine, Brigham & Women's Hospital, Boston, MA, USA.
Shamsudheen K VellarikkalThe Broad Institute of Harvard and MIT, Cambridge, MA, USA; Divisions of Genetics and Cardiovascular Medicine, Brigham & Women's Hospital, Boston, MA, USA.
Deepak S AtriThe Broad Institute of Harvard and MIT, Cambridge, MA, USA; Divisions of Genetics and Cardiovascular Medicine, Brigham & Women's Hospital, Boston, MA, USA.
Ankith ReddyDivisions of Genetics and Cardiovascular Medicine, Brigham & Women's Hospital, Boston, MA, USA.
Qiaohan XuOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.
Andrew R HamelThe Broad Institute of Harvard and MIT, Cambridge, MA, USA; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Marie BillaudDivision of Cardiothoracic Surgery, Brigham & Women's Hospital, Boston, MA, USA.
Ayellet V SegrèThe Broad Institute of Harvard and MIT, Cambridge, MA, USA; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Rajat M GuptaThe Broad Institute of Harvard and MIT, Cambridge, MA, USA; Divisions of Genetics and Cardiovascular Medicine, Brigham & Women's Hospital, Boston, MA, USA. Electronic address: rgupta@bwh.harvard.edu.

Funding

Single-cell, multi-omic investigation of epicardial adipose and coronary endothelial dysfunction in type 1 diabetesU01DK142338 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI RAJAT M GUPTA, Amit Majithia · 2024 to 2026
$3.0M
A genetic approach to identify the common mechanisms of vascular diseaseDP2HL152423 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI GUPTA, RAJAT M · 2019 to 2022
$2.8M
High-throughput cellular genetics to connect noncoding variants to coronary artery disease genesR01HL164811 · NHLBI · BROAD INSTITUTE, INC. · PI JESSE M ENGREITZ, RAJAT M GUPTA · 2023 to 2026
$2.7M
Identifying the organotypic and disease-specific vascular cell populations by integrating single cell data with polygenic riskU01HL166060 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI GUPTA, RAJAT M, SEGRE, AYELLET VERED · 2022 to 2025
$2.2M
NHLBI NIH HHS DP2 HL152423NHLBI NIH HHS R01 HL164811NHLBI NIH HHS U01 HL166060NIDDK NIH HHS U01 DK142338
6 · The paper itself

Abstract

backgroundVascular diseases are accompanied by alterations in cellular phenotypes which underlie disease pathogenesis, with single-cell technologies aiding in the discovery of cellular heterogeneity among endothelial cell (EC) and vascular smooth muscle cell (VSMC) populations. In atherosclerotic disease, VSMCs are hypothesized to transition between contractile and synthetic states; however, the specific vascular subpopulations and intermediate cell states responsible for early vascular dysfunction remain unclear.

methodsWe integrated newly generated and published single-nuclear RNA-sequencing (snRNA-seq) datasets to analyze normal (n = 7), aneurysmal (n = 9), and atherosclerotic (n = 2) flash-frozen human ascending thoracic aortas. Cell types and subtypes were defined using both top marker genes and canonical gene markers. Disease enrichment and relevant cell types were identified using newly developed computational tools to integrate GWAS data from multiple vascular disease-relevant studies with the single nuclei aortic expression profiles.

resultsNuclear dissociation and snRNA-seq identified ten distinct transcriptomic clusters from the integrated analysis representing all major vascular cell populations. Three distinct VSMC populations emerged that exhibited differential expression of extracellular matrix, contractile and pro-proliferative genes. Aneurysmal specimens were enriched for one fibroblast and one VSMC subpopulation compared to healthy tissue. RNA-trajectory analysis inferred a phenotypic continuum of gene expression between VSMC A and VSMC B or C and between two of the identified fibroblast types. VSMCs and Fibroblast C exhibited the greatest cell type-specific enrichment of genes mapped to GWAS loci for coronary artery disease (CAD), blood pressure, and migraine. Cell type-specific enrichment scores were more robust among the transcriptional profiles from non-diseased vascular tissue.

conclusionsOur use of single-cell isolation and new computational methods prioritizes the cell types that most contribute to vascular disease pathogenesis. Specifically, tissue dissociation and single-nuclear transcriptomics better represent all vascular cell types, from which we demonstrate enrichment of pro-proliferative VSMCs in TAA and further implicate phenotypic switching as a likely pathologic mechanism. Integrated analysis of cell-specific gene expression and vascular disease GWAS data implicate genes and pathways associated with fibroblast and VSMC cell-state transitions.

Indexed as

Aorta, ThoracicAortic Aneurysm, ThoracicAtherosclerosisEndothelial CellsGene Expression ProfilingMuscle, Smooth, VascularMyocytes, Smooth MuscleSingle-Cell AnalysisTranscriptomeFemaleGenome-Wide Association StudyHumansMalePhenotypeRNA-Seq

Identifiers

PMID40120433
PMCPMC12984030

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.