Flow-induced reprogramming of endothelial cells in atherosclerosis
Ian A Tamargo1,2, Kyung In Baek1, Yerin Kim1
1Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA.
Insights
Disturbed blood flow reprogrammes endothelial cells, driving atherosclerosis. Understanding this process (FIRE) may reveal new therapeutic targets for cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Endothelial Cell Biology
- Mechanobiology
Background:
- Atherosclerosis remains a leading cause of death globally, necessitating novel therapeutic targets beyond current treatments.
- Atherosclerosis preferentially occurs in arterial regions with disturbed blood flow (low shear stress), unlike protected straight regions with stable flow.
- Endothelial cells are sensitive to blood flow, undergoing changes regulated by mechanosensors and signaling pathways.
Purpose of the Study:
- To review the emerging concept of disturbed-flow-induced reprogramming of endothelial cells (FIRE) as a pro-atherogenic mechanism.
- To highlight the role of endothelial cell reprogramming in the development of atherosclerosis.
- To identify potential novel therapeutic targets for atherosclerotic disease.
Main Methods:
- Review of existing literature on endothelial cell responses to blood flow.
- Analysis of studies using single-cell RNA sequencing and chromatin accessibility in mouse models.
- Examination of flow-induced changes in endothelial cell phenotype, including inflammation and transition states.
Main Results:
- Disturbed blood flow induces significant changes in endothelial cells, including inflammation, endothelial-to-mesenchymal transition, and immune cell-like transition.
- These cellular reprogramming events are linked to the development of atherosclerosis.
- Healthy endothelial cell phenotypes are altered to diseased ones under disturbed flow conditions.
Conclusions:
- Disturbed-flow-induced reprogramming of endothelial cells (FIRE) is a key mechanism promoting atherosclerosis.
- Understanding FIRE pathways is crucial for developing new strategies against cardiovascular diseases.
- Targeting flow-induced endothelial cell reprogramming offers a promising avenue for novel atherosclerosis therapies.
Abstract:
Atherosclerotic diseases such as myocardial infarction, ischaemic stroke and peripheral artery disease continue to be leading causes of death worldwide despite the success of treatments with cholesterol-lowering drugs and drug-eluting stents, raising the need to identify additional therapeutic targets. Interestingly, atherosclerosis preferentially develops in curved and branching arterial regions, where endothelial cells are exposed to disturbed blood flow with characteristic low-magnitude oscillatory shear stress. By contrast, straight arterial regions exposed to stable flow, which is associated with high-magnitude, unidirectional shear stress, are relatively well protected from the disease through shear-dependent, atheroprotective endothelial cell responses. Flow potently regulates structural, functional, transcriptomic, epigenomic and metabolic changes in endothelial cells through mechanosensors and mechanosignal transduction pathways. A study using single-cell RNA sequencing and chromatin accessibility analysis in a mouse model of flow-induced atherosclerosis demonstrated that disturbed flow reprogrammes arterial endothelial cells in situ from healthy phenotypes to diseased ones characterized by endothelial inflammation, endothelial-to-mesenchymal transition, endothelial-to-immune cell-like transition and metabolic changes. In this Review, we discuss this emerging concept of disturbed-flow-induced reprogramming of endothelial cells (FIRE) as a potential pro-atherogenic mechanism. Defining the flow-induced mechanisms through which endothelial cells are reprogrammed to promote atherosclerosis is a crucial area of research that could lead to the identification of novel therapeutic targets to combat the high prevalence of atherosclerotic disease.
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