Our Work

Identifying key factors in the development of atherosclerosis

A striking feature of the disease is that it occurs more frequently in some parts of the arterial system than others. Studying what causes this patchiness will identify rate-limiting steps in the development of the disease and in the long term may lead to new strategies for delaying or preventing the disease. Our research focuses on the exchange of macromolecules between blood and the arterial wall, on forces exerted on the wall by the blood, and on signalling molecules (such as FSTL1 and nitric oxide) that mediate between these two factors. See 10.3389/fbioe.2022.836680 for a review and https://www.youtube.com/watch?v=TjzHSNQL84I for a YouTube video.

Developing non-invasive methods for assessing heart failure

When the left ventricle contracts, a wave of increased blood pressure, blood velocity and vessel diameter propagates through the systemic arteries. When the ventricle relaxes, a wave of decreased pressure, velocity and diameter propagates in the same direction. These waves therefore contain information about the ability of the heart to contract and relax, which are impaired in systolic and diastolic heart failure, respectively. We are developing novel ultrasound-based methods for diagnosing and monitoring heart failure by measuring the intensity and timing of the waves. Our preclinical trial is described here: 10.1016/j.ultrasmedbio.2022.09.016

Studying endothelial properties in culture

A continuous sheet of endothelial cells lines the inner surface of the arterial wall; it provides a significant barrier to the transport of water and solutes between plasma and wall tissue. Monolayers of endothelial cells can be grown in culture and many groups have used them to investigate endothelial transport properties. However, the permeability of cultured endothelium is much higher than that of endothelium in vivo, making the results hard to interpret. We have reduced permeabilities by exposing the monolayers to mechanical stresses and to other cell types. The results are useful for studying transport in vitro but also suggest factors that control permeability in vivo. Because atherosclerosis may be triggered by multidirectional flow, we have modified and analysed the “swirling well” (or orbital shaker) method which allows such flows to be chronically applied to cultured endothelium - see our review at 10.1016/j.atherosclerosis.2019.04.210

Determining scaling laws in cardiovascular mechanics

Arterial disease has a different distribution in mice than in rabbits and people. Furthermore, blood flow exerts very different stresses on the arterial wall in these species. These observations motivated us to investigate scaling laws – how cardiovascular properties differ in magnitude between animals of different size. The results suggest new concepts concerning the response of endothelial cells to mechanical forces - see 10.1016/j.jbiomech.2006.07.020.

Investigating the role of arterial wall transport in the development of vulnerable plaques

Exchange of material between blood and the arterial wall seems to be a key factor in the initiation of atherosclerotic lesions; it depends on blood flow and nitric oxide or FSTL1 signalling. As these early lesions grow, they can remain stable and benign, or they can develop into unstable (“vulnerable”) lesions with a large lipid-rich core that are prone to rupture, precipitating clinical events. We have provided evidence that early lesions can develop into unstable plaques because of excessive wall uptake of plasma lipoproteins and that this uptake again depends on flow and nitric oxide - see 10.1371/journal.pone.0115728.

Identifying determinants of the aggregation and oxidation of LDL

Low density lipoprotein (LDL), the major carrier of cholesterol, needs to be modified before it accumulates excessively in the arterial wall; oxidation and aggregation appear to be the most important modifications. LDL is prone to aggregation in laboratory stirrers but not in the blood stream; we have shown this is due to a complex interplay of mechanical and biochemical factors. We have also shown that oxidised LDL accumulates in the arterial wall at sites showing an excessive permeability for unmodified LDL, implying that the rate of entry rather than the rate of oxidation is the limiting step. In a project led by Professor D S Leake, we are currently studying whether the oxidation of LDL within the wall occurs inside lysosomes and can be inhibited by cysteamine - see 10.1016/j.atherosclerosis.2019.09.019

Earlier projects

The group has also studied the influence of micronutrients on atherogenic processes, the physical chemistry of connective tissues and FTIR and SICM imaging of arterial tissue. These projects are currently inactive.