Plaque erosion

Research Team

Dr Sarah Jones
Dr Amanda Unsworth

We are developing more physiological and disease relevant in vitro models of thrombosis to enable us to better understand the pathologies of plaque rupture and erosion.

Dr Sarah Jones

Senior Lecturer

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Our research is focussed on understanding how platelets contribute to plaque formation to enable us to develop more effect anti-thrombotic therapies

Dr Amanda Unsworth

Senior Lecturer

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About our research

The majority of heart attacks are caused by a blood clot that develops over the top of a disrupted atherosclerotic plaque in one of the arteries that supply the heart muscle with blood.

Two thirds occur because the plaque physically breaks open, or ruptures, while the remainder are mostly caused when the endothelial layer that lines the artery is disrupted over the plaque. Both events expose the artery wall, triggering platelet adhesion and coagulation and a process called thrombosis.

We work on the two processes that promote plaque erosion:

altered endothelial biology
altered plaque composition

30%

of acute coronary syndromes are caused by Endothelial erosion of atherosclerotic plaques and resulting thrombosis.

An illustration of plaque obstructing blood flow.

Altered endothelial biology

Endothelial cell behaviour is particularly driven by the blood flow pattern to which it is exposed. This is the basis for the focal development of atherosclerosis, which predominantly develops at branch points in arteries, where the endothelium is exposed to disturbed blood flow.

In contrast, plaque erosion most frequently occurs on stenotic plaques in areas of elevated flow. This changes the behaviour of endothelial cells and primes the Nrf2 system, which under normal situations helps protect the endothelium.

Smoking is a known risk factor for plaque erosion. We have shown that smoking hyperactivates the Nrf2 system, upregulating the expression of OSGIN1+2 and promoting endothelial detachment. We also have initial leads on compounds that might inhibit plaque erosion.

Elevated flow and smoking can trigger endothelial detachment. Computational fluid dynamic (CFD) assessment of eroded plaques in patients identified that plaque erosion frequently occurs proximal to, or within, the point of maximum stenosis, exposing the endothelium to elevated flow.

Elevated flow modifies endothelial phenotype, which on exposure to soluble factors from cigarette smoke and the inflammatory cytokine TNFα highly activate the transcription factor Nrf2 and the expression of OSGIN1 and 2. This induces detachment of human coronary artery endothelial cells, which can be rescued by inhibition of HSP70 and AMPK activation.

Academic papers

Satta, S, Mahmoud, AM, Wilkinson, FL, Alexander, MY and White, SJ (2017) The Role of Nrf2 in Cardiovascular Function and Disease, Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 9237263, 18 pages
Satta, S, et al A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques
McElroy, M, Kim, Y, Niccoli, G et al(2021) Identification of the haemodynamic environment permissive for plaque erosion. Sci Rep, 11,7253

Altered plaque composition

One observation that has been made from pathology examination of eroded plaques is a unique composition of the underlying plaque matrix underneath the thrombus.

We have systematically probed various vascular risk factors for their ability to alter the production of extracellular matrix in a way that matches that found in eroded plaques. We are using this to examine the mechanism of control and the influence of this altered matrix on endothelial behaviour.

This research is also enriching our studies, funded by NC3Rs, to develop thrombosis models that mirror the effects of plaque rupture and erosion.