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 nitric oxide) that mediate between these two factors.
Developing non-invasive methods for assessing arterial nitric oxide bioactivity
Our interest in arterial nitric oxide signalling led us to develop techniques for measuring it in vivo. Since dysfunction of the nitric oxide pathway dramatically increases the risk of cardiovascular disease, a simple, non-invasive technique for assessing it would be of great value in the clinic, as well as for own research. The methods we are developing depend on analysing the way blood pressure or blood volume in peripheral arteries varies during each heart beat.
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.
Determining scaling laws in cardiovascular mechanics
Arterial lesions in mice and rabbits have different distributions. Furthermore, blood flow exerts very different stresses on the arterial wall in these two 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.
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 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 are testing whether early lesions develop into unstable plaques because of excessive wall uptake of plasma lipoproteins and whether this uptake again depends on flow and nitric oxide.
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. We are currently studying whether the oxidation of LDL within the wall occurs inside cells and not, as commonly assumed, in the extracellular space.