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Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes

Abstract

Flowing blood generates a frictional force called shear stress that has major effects on vascular function. Branches and bends of arteries are exposed to complex blood flow patterns that exert low or low oscillatory shear stress, a mechanical environment that promotes vascular dysfunction and atherosclerosis. Conversely, physiologically high shear stress is protective. Endothelial cells are critical sensors of shear stress but the mechanisms by which they decode complex shear stress environments to regulate physiological and pathophysiological responses remain incompletely understood. Several laboratories have advanced this field by integrating specialized shear-stress models with systems biology approaches, including transcriptome, methylome and proteome profiling and functional screening platforms, for unbiased identification of novel mechanosensitive signalling pathways in arteries. In this Review, we describe these studies, which reveal that shear stress regulates diverse processes and demonstrate that multiple pathways classically known to be involved in embryonic development, such as BMP–TGFβ, WNT, Notch, HIF1α, TWIST1 and HOX family genes, are regulated by shear stress in arteries in adults. We propose that mechanical activation of these pathways evolved to orchestrate vascular development but also drives atherosclerosis in low shear stress regions of adult arteries.

Key points

  • Shear stress regulates atherosclerosis by altering endothelial cell physiology.

  • Systems biology approaches have identified multiple shear stress-regulated pathways in the endothelium, including several pathways classically known to be involved in embryogenesis.

  • Blood flow-mediated regulation of developmental pathways orchestrates valve formation and angiogenesis to optimize tissue perfusion.

  • By contrast, in arteries in adults, these blood flow-regulated pathways lead to inflammation, vascular dysfunction and atherosclerosis.

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Fig. 1: In vivo manipulation of shear stress.
Fig. 2: Systems biology approach to identify mechanosensitive pathways in vascular endothelium.
Fig. 3: Flow regulation of vascular development.
Fig. 4: Flow regulation of valve development.
Fig. 5: Low shear stress activation of a network that drives angiogenesis and atherosclerosis.

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Acknowledgements

The authors are funded by the British Heart Foundation, Medical Research Council and the National Centre for the Replacement, Refinement and Reduction of Animals in Research.

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Glossary

DNA methylome

A set of DNA methylation modifications that vary between cell types and according to physiological context.

Endothelial-to-mesenchymal transition

A process of endothelial cell plasticity that leads to a mesenchymal state.

Differentially methylated regions

Regions of the genome that exhibit differences in DNA methylation status across different biological samples.

Reduced-representation bisulfite sequencing

Method for mapping whole-genome DNA methylation that is based on sequencing CpG-rich regions and involves methylation-sensitive conversion of cytosines to uracils (methylcytosines are not converted) with the use of sodium bisulfate followed by next-generation sequencing.

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Souilhol, C., Serbanovic-Canic, J., Fragiadaki, M. et al. Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes. Nat Rev Cardiol 17, 52–63 (2020). https://doi.org/10.1038/s41569-019-0239-5

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