Endothelial Reprogramming by Disturbed Flow Revealed by Single-Cell RNA and Chromatin Accessibility Study

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Genomics

Background:

• Atherosclerosis is linked to disturbed blood flow (d-flow) impacting endothelial cells (ECs).
• Understanding the molecular mechanisms of EC response to d-flow is crucial for atherosclerosis research.

Purpose of the Study:

• To investigate the heterogeneity and plasticity of endothelial cells under disturbed flow conditions.
• To identify transcription factors and cellular phenotypes associated with d-flow-induced atherosclerosis.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) and scATAC-seq on mouse carotid artery ECs.
• Utilized the partial carotid ligation (PCL) mouse model to induce d-flow.
• Bioinformatic analyses including marker gene identification, pathway analysis, and pseudotime analysis.

Main Results:

• Identified eight distinct EC clusters, along with other cell types, showing EC heterogeneity.
• Demonstrated that d-flow induces ECs to transition from atheroprotective to pro-inflammatory, mesenchymal (EndMT), and immune cell-like (EndICLT) phenotypes.
• Identified transcription factors RELA, AP1, STAT1, and TEAD1 as sensitive to d-flow, contrasting with KLF4/KLF2 sensitive to stable flow.

Conclusions:

• Endothelial cells exhibit significant heterogeneity and plasticity in response to disturbed flow.
• Disturbed flow actively reprograms endothelial cells towards proatherogenic states, including EndMT and EndICLT.
• The identified transcription factors provide potential targets for therapeutic interventions against d-flow-induced atherosclerosis.