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Cardiovascular disease

A turbulent path to plaque formation

Nature volume 540, pages 531532 (22 December 2016) | Download Citation

Plaque deposits often occur in curved arterial regions with turbulent blood flow. Endothelial cells have been found to respond to blood flow through a previously unidentified signalling pathway that affects plaque build-up. See Letter p.579

A key characteristic of the disease atherosclerosis is the gradual accumulation of plaque deposits on the walls of arteries. Plaque is composed of cellular waste, fatty deposits and cholesterol molecules, and is not uniformly distributed in arteries1. Some plaques can reach a size that obstructs blood flow to organs, causing heart attacks or strokes2. On page 579, Wang et al.3 propose a mechanism for plaque development that also provides an explanation for plaque-formation patterns.

Blood-flow dynamics have a central role in atherosclerosis development, and the key driving force is shear stress4: the frictional force exerted on blood-vessel walls because of blood flow. Shear stress as a result of the uniform laminar blood flow that occurs in straight regions of blood vessels is not considered to be a risk factor for plaque formation4. However, curved blood-vessel regions, including branch points, have disturbed (turbulent) blood-flow patterns and are more susceptible to plaque development4.

How do differences in the mechanical forces exerted on blood vessels result in the promotion or inhibition of plaque formation? Endothelial cells line blood-vessel walls and can sense and distinguish laminar and disturbed blood-flow patterns, which results in changes to endothelial signalling pathways that ultimately determine whether plaque formation is promoted or inhibited4.

YAP and TAZ proteins act as cellular sensors or checkpoints for mechanical forces5. These proteins are also master regulators in the Hippo-protein-mediated signalling pathway, which controls organ size and has a tumour-suppressor function6. In atherosclerotic arteries, two of the genes transcribed through the actions of YAP and TAZ are highly expressed7,8; however, direct evidence that links YAP and TAZ to the sensing of mechanical force by endothelial cells and to the development of atherosclerosis has been lacking.

Activation of the YAP and TAZ pathway can be measured by assaying phosphorylation of YAP, movement of the proteins into the nucleus or the expression of their target genes. Using all three assays, Wang et al. observed the inhibition of YAP and TAZ activity when endothelial cells grown in vitro were subjected to uniform, laminar shear stress. By contrast, YAP and TAZ activity was high when these cells were exposed to disturbed shear stress (Fig. 1).

Figure 1: Endothelial-cell signalling can affect plaque formation.
Figure 1

Laminar blood flow parallel to the blood-vessel wall usually occurs in straight regions of arteries. Disturbed, non-laminar blood flow occurs in curved arterial regions, including where a vessel branches. The endothelial cells that line blood vessels can sense and respond to these two different types of blood flow4. Regions of disturbed blood flow are associated with deposits of plaque, an accumulation of cellular waste and fatty molecules that can obstruct blood flow and potentially cause disease. Wang et al.3 report that, in experiments using mouse models and human tissue, endothelial cells adjacent to disturbed blood flow had high YAP and TAZ activity and increased plaque formation. By contrast, endothelial cells adjacent to laminar blood flow have low YAP and TAZ activity and do not have plaque deposits.

Wang and colleagues confirmed that YAP and TAZ activity is regulated by blood flow, using an in vivo system in which the abdominal artery in rats is clamped. This constriction generates regions of uniform and disturbed shear stress in the same blood vessel9. High YAP activity was observed where blood flow was disturbed, and low YAP activity was seen in a region subjected to high uniform shear stress.

To determine whether their findings were relevant to atherosclerosis in vivo, Wang and colleagues used a mouse model of atherosclerosis. These animals lack a protein that affects cholesterol metabolism and are susceptible to plaque formation when fed a high-fat diet10. The mice that developed atherosclerotic plaques had high YAP and TAZ activity in their arteries. The authors also examined samples of human atherosclerotic blood vessels and saw similar high YAP and TAZ activity.

The authors then tested whether manipulating the level of YAP affects plaque formation. Using a version of the atherosclerotic mouse model in which YAP was overexpressed in endothelial cells, they observed that, after four weeks on a high-fat diet, the mice had significantly increased plaque formation as compared with control animals.

To determine the role of YAP in atherosclerosis mediated by disturbed blood flow, the authors subjected atherosclerotic mice10 to disturbed shear stress through surgery to the carotid artery11. In this system, mice that had also been genetically engineered to have lower endothelial YAP expression had significantly less atherosclerosis than did control animals. Lower atherosclerosis, as compared with control mice, was also seen if the gene expression of TAZ rather than YAP was decreased.

Wang et al. propose that the laminar-shear-stress pathway that inhibits YAP and TAZ comprises several molecules that participate in the process of mechanotransduction — the mechanism by which cells convert mechanical signals into biochemical responses. The authors found that laminar shear stress promotes the activation of integrin proteins, promotes the interaction between integrin β3 and the Gα13 protein and inhibits the protein RhoA, and that these signalling changes subsequently lead to YAP inactivation. Integrin β3 also has a plaque-promoting role12,13,14, but how this relates to the plaque-inhibiting role identified by Wang and colleagues is unknown and needs to be investigated.

To explore the plaque-promoting signalling pathways associated with YAP and TAZ activation, Wang and colleagues conducted cellular analyses, including the analysis of messenger RNA sequences. This revealed that YAP and TAZ promote the activation of several inflammatory pathways, including the atherosclerosis-promoting JNK-protein pathway. It is well established that atherosclerosis is a multifactorial disease in which inflammation has a crucial role.

Drugs that lower cholesterol to prevent plaque formation are the most commonly prescribed medicines in Western countries, and are a first-line therapy for people who have cardiovascular disease. Cholesterol-lowering statin drugs regulate the YAP and TAZ pathway15,16. Whether these drugs protect against plaque formation through modulation of the YAP and TAZ pathway was unknown.

Wang and colleagues treated human cells that express constantly active YAP and TAZ in vitro with the statin simvastatin. They found that the treatment did not suppress YAP/TAZ-dependent expression of key genes that promote inflammation and atherosclerosis, indicating that the anti-inflammatory and anti-plaque effects of statins are probably mediated by inhibition of YAP and TAZ activity. This indicates that the YAP and TAZ pathway could be considered as a treatment target for atherosclerosis.

Atherosclerosis is a complex disease in which associated inflammation probably occurs through several different pathways, and this complexity presents an obstacle to successful clinical treatment. Is it possible to target YAP and TAZ specifically in endothelial cells in the arteries? Is suppression of just YAP and TAZ, or the molecules within the YAP and TAZ signalling pathway, sufficient to ameliorate atherosclerosis? Does targeting the pathway also affect the tumour-suppressing function of the Hippo pathway? These questions need to be answered before a therapy to prevent atherosclerosis can be devised on the basis of YAP and TAZ inhibition.

Notes

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  1. Vedanta Mehta and Ellie Tzima are at the Wellcome Trust Centre for Human Genetics, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.

    • Vedanta Mehta
    •  & Ellie Tzima

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Correspondence to Ellie Tzima.

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