Role of Flow-Sensitive Endothelial Genes in Atherosclerosis and Antiatherogenic Therapeutics Development
Kyung In Baek1, Kitae Ryu2,3
1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
Insights
Blood flow patterns significantly impact atherosclerosis development by altering endothelial cell gene expression. Disturbed flow promotes pro-atherogenic changes, highlighting flow-sensitive genes as therapeutic targets.
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Biomedical Engineering
Background:
- Atherosclerosis is a chronic inflammatory disease underlying cardiovascular disease.
- Endothelial dysfunction, influenced by genetic and environmental factors like blood flow, initiates atherosclerosis.
- Specific arterial regions exposed to disturbed blood flow are prone to atherosclerosis, unlike those with stable flow.
Purpose of the Study:
- To investigate how biomechanical forces, specifically blood flow patterns, influence endothelial cell (EC) behavior.
- To understand the genome- and epigenome-wide changes in ECs induced by disturbed flow.
- To identify flow-sensitive genes and proteins as potential targets for antiatherogenic therapies.
Main Methods:
- Analysis of endothelial cells (ECs) from arterial regions exposed to stable versus disturbed blood flow.
- Genome-wide and epigenome-wide analysis of gene expression changes in ECs.
- Correlation of gene expression changes with atherosclerosis development and risk factors.
Main Results:
- Disturbed blood flow induces significant changes in EC gene expression compared to stable flow.
- These changes reprogram ECs from an athero-protected state to a pro-atherogenic state.
- Flow-induced EC reprogramming, combined with factors like hypercholesterolemia, drives atherosclerosis progression.
Conclusions:
- Blood flow patterns are critical regulators of endothelial cell phenotype in atherosclerosis.
- Flow-sensitive genes and proteins represent key mechanisms in atherosclerosis development.
- Targeting these flow-sensitive elements offers a novel therapeutic strategy against atherosclerosis.
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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