Faculty, Staff and Student Publications

Language

English

Publication Date

9-30-2024

Journal

Annals of the Rheumatic Diseases

DOI

10.1136/ard-2023-225415

PMID

38754983

PMCID

PMC11442142

PubMedCentral® Posted Date

3-30-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Objectives: Vasculopathy emerges early in systemic sclerosis (SSc) and links to endothelial cell (EC) injury and angiogenesis. Understanding EC transcriptomes and epigenomes is crucial for unravelling the mechanisms involved.

Methods: Transcriptomes and chromatin accessibility were assessed by single-cell RNA sequencing and single-nucleus transposase-accessible chromatin sequencing. Immunofluorescent staining of skin and proteomics assay were employed to confirm the altered SSc EC phenotypes. Gain-of-function assay was used to evaluate the effects of ETS transcription factors on human dermal ECs (hDECs).

Results: Both control and SSc ECs shared transcriptomic signatures of vascular linages (arterial, capillary and venous ECs) and lymphatic ECs. Arterial ECs in SSc showed reduced number and increased expression of genes associated with apoptosis. Two distinct EC subpopulations, tip and proliferating ECs, were markedly upregulated in SSc, indicating enhanced proangiogenic and proliferative activities. Molecular features of aberrant SSc-ECs were associated with disease pathogenesis and clinical traits of SSc, such as skin fibrosis and digital ulcers. Ligand-receptor analysis demonstrated altered intercellular networks of SSc EC subpopulations with perivascular and immune cells. Furthermore, the integration of open chromatin profiles with transcriptomic analysis suggested an increased accessibility of regulatory elements for ETS family transcription factors in SSc ECs. Overexpression of ETS genes in hDECs suggested ELK4, ERF and ETS1 may orchestrate arterial apoptosis and dysregulated angiogenesis in SSc.

Conclusions: This study unveils transcriptional and chromatin alterations in driving endovascular dysregulation in SSc, proposing ELK4, ERF and ETS1 as novel targets in ECs for addressing vascular complications in the condition.

Keywords

Humans, Scleroderma, Systemic, Endothelial Cells, Transcriptome, Single-Cell Analysis, Neovascularization, Pathologic, Chromatin, Transcription Factors, Female, Male, Middle Aged, Skin, Adult, Apoptosis, Angiogenesis, Systemic sclerosis (SSc), Endothelial cells (ECs), Single-cell RNA sequencing (scRNA-seq), Single-nucleus transposase-accessible chromatin sequencing (snATAC-seq), ETS transcription factors

Published Open-Access

yes

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