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Role of Flow-Sensitive Endothelial Genes in Atherosclerosis and Antiatherogenic Therapeutics Development

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Abstract

Atherosclerosis is a chronic inflammatory disease that is the underlying cause of cardiovascular disease which initiates from endothelial dysfunction from genetic and environmental risk factors, including biomechanical forces: blood flow. Endothelial cells (ECs) lining the inner arterial wall regions exposed to disturbed flow are prone to atherosclerosis development, whereas the straight regions exposed to stable flow are spared from the disease. These flow patterns induce genome- and epigenome-wide changes in gene expression in ECs. Through the sweeping changes in gene expression, disturbed flow reprograms ECs from athero-protected cell types under the stable flow condition to pro-atherogenic cell conditions. The pro-atherogenic changes induced by disturbed flow, in combination with additional risk factors such as hypercholesterolemia, lead to the progression of atherosclerosis. The flow-sensitive genes and proteins are critical in understanding the mechanisms and serve as novel targets for antiatherogenic therapeutics.

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Fig. 1

Modified from Kumar et al., created with BioRender.com. Abbreviations: D-flow, disturbed flow; EC, endothelial cell; LDL, low-density lipoprotein; oxLDL, oxidized LDL; S-flow, stable flow; VSMC, vascular smooth muscle cell

Fig. 2
Fig. 3

Modified from Cheng et al., 2017, created with BioRender.com Abbreviations: D-flow, disturbed flow; EC, endothelial cell; ECM, extracellular matrix; MWSS, mean wall shear stress

Fig. 4

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

S-flow:

Stable flow

D-flow:

Disturbed flow

EC:

Endothelial cells

LAM:

Leukocyte adhesion molecule

VCAM1:

Vascular adhesion molecule 1

MMP:

Metalloproteinases

BMP4:

Bone morphogenic protein

miR:

Micro RNAs

EndMT:

Endothelial to mesenchymal transition

EndICLT:

Endothelial to immune cell-like transition

ECM:

Extracellular matrix

NO:

Nitic oxide

ROS:

Reactive oxygen species

SMA:

Smooth muscle actin

scATACseq:

Single cell assay for transposase-accessible chromatin using sequencing

EndICLT:

Endothelial cell-immune cell-like transition

LDL:

Low-density lipoprotein

oxLDL:

Oxidized LDL

LRP1:

Lipoprotein receptor-related protein 1

LOX1:

Lectin-like oxLDL 1 receptor

VSMC:

Vascular smooth muscle cells

IFNγ:

Interferonγ

WSS:

Wall shear stress

MWSS:

Mean WSS

Re:

Reynold’s number

TNF:

Tumor necrosis factor

KLF2:

Krüppel-like factor 2

KLF4:

Krüppel-like factor 4

Par1:

Protease-activated receptor 1

Jnk:

JUN N-terminal kinase

ATF2:

Activating transcription factor 2

eNOS:

Endothelial nitric oxide synthase

TGF β:

Transforming growth factor β

FSP1:

Fibroblast-specific protein 1

vWF:

Von willlebrand factor

AV:

Aortic valve

VEC:

Valvular EC

CYR61:

Cysteine-rich angiogenic inducer 61

CTGF:

Connective tissue growth factor

ANKRD1:

Ankyrin repeat domain 1

LATS:

Large tumor suppressor

HIF-1α:

Hypoxia inducible factor 1-alpha

pVHL:

Von Hippel-Lindau protein

PS:

Pulsatile shear

MYH11:

Myosin heavy chain

ABCA1:

ATP-binding cassette transporter A1

IL-10:

Interleukin-10

HBP1:

HMG box-transcription protein 1

MIF:

Migration inhibitory factor

MCP-1:

Monocyte chemoattractant protein-1

ITGA5:

Integrin subunits α5

HAEC:

Human aortic endothelial cells

OS:

Oscillatory shear

LS:

Laminar shear

iMAEC:

Immortalized mouse aortic endothelial cells

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Acknowledgements

This study is supported by the National Institutes of Health 5T32HL007745-28 (KB).

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National Institutes of Health, 5T32HL007745-28, Kyung In Baek

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  1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA

    Kyung In Baek & Kitae Ryu

  2. Department of Biotechnology, The University of Suwon, 17, Wauan-Gil, Bongdam-Eup, Hwaseong-Si, Gyeonggi-Do, 18323, Republic of Korea

    Kitae Ryu

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  1. Kyung In Baek
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Baek, K.I., Ryu, K. Role of Flow-Sensitive Endothelial Genes in Atherosclerosis and Antiatherogenic Therapeutics Development. J. of Cardiovasc. Trans. Res. (2023). https://doi.org/10.1007/s12265-023-10463-w

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