Final Report Summary - LDLTRAPPING (Identifying causes of lipoprotein trapping in arteries)
Transport of material through the arterial wall remains poorly characterised, despite the clear clinical and commercial importance. For example understanding protein uptake in the wall can shed light on the mechanisms leading to atherosclerosis or can help optimise drug delivery for disease treatment. The key issue is that many of the details of transport are elusive and no reliable method of measurement is available.
In this project, we have developed novel combined numerical-experimental approaches to characterise water transport in the medial layer of the arterial wall and how the deformation of the artery (due to the pressure pulse induced by the beating heart) influences reorganisation of the microstructure and local straining of the tissue. In our initial work we introduced a novel approach combining confocal microscopy data with a computer model of transport through the medial tissue of the arterial wall. The media consists of cells, water, and structural molecules - principally glycosaminoglycans, collagen and elastin. These components are not randomly associated but have a lamellar architecture. Water and dissolved solutes crossing the media do not have access to all these compartments; they are certainly excluded by cells and partially excluded, to differing extents, by the other components. In essence this layer can be thought of being much like a sponge, which the cells (the air pockets of the sponge) reorganise affecting the transport. Figure 1 shows the typical structure of the arterial media.
The structure in Figure 1 is obtained from arterial tissue that has been bathed in a solution of fluorescent protein tracer and the proteins fixed in the structure following perfusion with formaldehyde. This structure is then embedded with epoxy resin and scanned on a laser scanning confocal microscope. Using the confocal images, we have devised a novel method to determine the permeability, which is a measure of how easily water flows through a porous structure, and the preferential directions that water flows through the layer. Important results were that the transport in the media is naturally reduced at the inner media (the internal side of the arterial wall). Furthermore, the permeability of the media varies due to the alignment and density of smooth muscle cells throughout the structure.
Recently, we have further developed our initial approach to take into account the deformation of the arterial wall. In this method the imaged structure is obtained from confocal imaging after the structure has been fixed at different pressures (40, 80, 100 and 120mmHg – the latter 3 pressures are the normal physiological range). Using our developed approach we have shown that the permeability in the radial direction of the rat aortic artery (from the inner to the outer side) decreases rapidly between 80 and 100mmHg, whilst the permeability in the axial (along the vessel) and circumferential (around the vessel) directions does not decrease until between 100 and 120mmHg. Furthermore the permeability in the radial direction is up to 3 times lower, depending on the pressure, than the other directions. These observations could help us understand and better characterise transport of drugs that enter the arterial wall to treat diseased locations. From these observations we have been able to determine how permeability varies with local straining in the arterial wall. This is very important as our results suggest that transport across the medial layer varies significantly depending on how much the tissue is strained. In particular we have developed a new constitutive relationship (relating the permeability to the local strain in the arterial wall) that enables us to understand how deformation of the wall (left hand image in Figure 3) induces differing levels of water transport (right hand image in Figure 3) through the wall.
Overall the project has been very successful and made a significant contribution to the field of arterial biomechanics. The project has highlighted that water transport, and by implication protein transport, varies spatially in the arterial with many implications for transport of proteins during the initiation of atherosclerosis and drug transport for novel treatments of the disease.
In this project, we have developed novel combined numerical-experimental approaches to characterise water transport in the medial layer of the arterial wall and how the deformation of the artery (due to the pressure pulse induced by the beating heart) influences reorganisation of the microstructure and local straining of the tissue. In our initial work we introduced a novel approach combining confocal microscopy data with a computer model of transport through the medial tissue of the arterial wall. The media consists of cells, water, and structural molecules - principally glycosaminoglycans, collagen and elastin. These components are not randomly associated but have a lamellar architecture. Water and dissolved solutes crossing the media do not have access to all these compartments; they are certainly excluded by cells and partially excluded, to differing extents, by the other components. In essence this layer can be thought of being much like a sponge, which the cells (the air pockets of the sponge) reorganise affecting the transport. Figure 1 shows the typical structure of the arterial media.
The structure in Figure 1 is obtained from arterial tissue that has been bathed in a solution of fluorescent protein tracer and the proteins fixed in the structure following perfusion with formaldehyde. This structure is then embedded with epoxy resin and scanned on a laser scanning confocal microscope. Using the confocal images, we have devised a novel method to determine the permeability, which is a measure of how easily water flows through a porous structure, and the preferential directions that water flows through the layer. Important results were that the transport in the media is naturally reduced at the inner media (the internal side of the arterial wall). Furthermore, the permeability of the media varies due to the alignment and density of smooth muscle cells throughout the structure.
Recently, we have further developed our initial approach to take into account the deformation of the arterial wall. In this method the imaged structure is obtained from confocal imaging after the structure has been fixed at different pressures (40, 80, 100 and 120mmHg – the latter 3 pressures are the normal physiological range). Using our developed approach we have shown that the permeability in the radial direction of the rat aortic artery (from the inner to the outer side) decreases rapidly between 80 and 100mmHg, whilst the permeability in the axial (along the vessel) and circumferential (around the vessel) directions does not decrease until between 100 and 120mmHg. Furthermore the permeability in the radial direction is up to 3 times lower, depending on the pressure, than the other directions. These observations could help us understand and better characterise transport of drugs that enter the arterial wall to treat diseased locations. From these observations we have been able to determine how permeability varies with local straining in the arterial wall. This is very important as our results suggest that transport across the medial layer varies significantly depending on how much the tissue is strained. In particular we have developed a new constitutive relationship (relating the permeability to the local strain in the arterial wall) that enables us to understand how deformation of the wall (left hand image in Figure 3) induces differing levels of water transport (right hand image in Figure 3) through the wall.
Overall the project has been very successful and made a significant contribution to the field of arterial biomechanics. The project has highlighted that water transport, and by implication protein transport, varies spatially in the arterial with many implications for transport of proteins during the initiation of atherosclerosis and drug transport for novel treatments of the disease.
