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bioRxiv · 10.1101/2020.07.15.205427

Endothelial reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study

Andueza, A.·Kumar, S.·Kim, J.·Kang, D. W.·Mumme, H. L.·Perez, J. I.·Jo, H.
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Abstract

Disturbed flow (d-flow) induces atherosclerosis by regulating gene expression in endothelial cells (ECs). For further mechanistic understanding, we carried out a single-cell RNA sequencing (scRNAseq) and scATACseq study using endothelial-enriched single-cells from the left- and right carotid artery exposed to d-flow (LCA) and stable-flow (s-flow in RCA) using the mouse partial carotid ligation (PCL) model. We found 8 EC clusters along with immune cells, fibroblasts, and smooth muscle cells. Analyses of marker genes, pathways, and pseudo-time revealed that ECs are highly heterogeneous and plastic. D-flow induced a dramatic transition of ECs from atheroprotective phenotypes to pro-inflammatory, mesenchymal (EndMT), hematopoietic stem cells, endothelial stem/progenitor cells, and an unexpected immune cell-like (EndICLT) phenotypes. While confirming KLF4/KLF2 as s-flow-sensitive transcription factor binding site, we also found those sensitive to d-flow (RELA, AP1, STAT1, and TEAD1). D-flow reprograms ECs from atheroprotective to pro-atherogenic phenotypes including EndMT and potentially EndICLT.

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Andueza, A., Kumar, S., Kim, J., Kang, D. W., Mumme, H. L., Perez, J. I., Jo, H.. 2020-07-15. Endothelial reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study. https://doi.org/10.1101/2020.07.15.205427

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