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Mechanotransduction in vascular physiology and atherogenesis

Key Points

  • Fluid shear stress from blood flow and circumferential stretch of vessel walls from blood pressure are important regulatory factors that control the morphogenesis and physiology of blood vessels. However, atherosclerosis initiates at regions of arteries that, owing to vessel anatomy, develop disturbances in flow patterns.

  • Mechanical forces from blood flow are exerted on many different structural elements in the cell. A number of these might transduce forces into biochemical signals that regulate cellular responses.

  • Disturbed fluid shear stress activates the vascular endothelium to initiate atherosclerosis, mainly because cells cannot adapt to these flow patterns and cannot downregulate signalling pathways. Changes in gene expression and the endothelial extracellular matrix help entrain the activated state to cause life-long chronic inflammation.

  • Systemic risk factors, such as high cholesterol and blood pressure, synergize with disturbed flow to promote the progression of atherosclerosis.

  • These ideas suggest that atherosclerosis arises because the normal physiological responses to laminar flow have unintended consequences in the face of disturbed flow.

Abstract

Forces that are associated with blood flow are major determinants of vascular morphogenesis and physiology. Blood flow is crucial for blood vessel development during embryogenesis and for regulation of vessel diameter in adult life. It is also a key factor in atherosclerosis, which, despite the systemic nature of major risk factors, occurs mainly in regions of arteries that experience disturbances in fluid flow. Recent data have highlighted the potential endothelial mechanotransducers that might mediate responses to blood flow, the effects of atheroprotective rather than atherogenic flow, the mechanisms that contribute to the progression of the disease and how systemic factors interact with flow patterns to cause atherosclerosis.

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Figure 1: Mechanical forces on the vessel wall.
Figure 2: Vascular bifurcation and flow patterns.
Figure 3: Endothelial mechanotransducers.
Figure 4: Time course of endothelial activation.

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Acknowledgements

Work from the laboratory of M.S. was supported by National Institutes of Health grants RO1 HL75092 and 80956 to MAS.

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Glossary

Shear stress

The frictional force per unit area that a fluid exerts as it flows over a surface. This force is parallel to the surface and is proportional to the viscosity and the velocity of the fluid, and is inversely proportional to the radius of the vessel.

Blood pressure

The hydraulic pressure (force per area) in the blood vessels that results from the pumping action of the heart. Blood pressure is highest in the aorta and decreases as blood travels into smaller arteries, capillaries and then veins. Blood pressure exerts a force that causes a circumferential stretch of the vessel wall.

Hyperlipidaemia

The state of blood carrying high levels of lipoproteins that contain cholesterol and triglycerides.

Laplace's law

This law states that tension in the vessel wall equals the difference in pressure across the vessel times the radius of the vessel, divided by the thickness of the wall. Thus, higher blood pressure or vessels of larger radius require thicker walls to be mechanically stable.

Nephron

The kidney consists of millions of these functional units. Each nephron begins with a glomerulus, in which blood is filtered through a specialized basement membrane. The resultant cell-free fluid enters a tube that is lined with epithelial cells that transport valuable components back into the blood, with the remainder excreted as urine.

Foam cell

A macrophage in the artery wall that has become engorged with cholesterol esters and triglycerides.

Apolipoprotein E

An important constituent of the high density lipoprotein, which carries 'good' cholesterol from the tissues to the liver.

Vasorelaxation

The release of factors, such as nitric oxide, by the endothelium causes relaxation of the smooth muscle layer, leading to widening of the artery lumen.

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Hahn, C., Schwartz, M. Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10, 53–62 (2009). https://doi.org/10.1038/nrm2596

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