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Abstract
Background and aimsTransport of macromolecules between plasma and the arterial wall plays a key role in atherogenesis. Scattered hotspots of elevated endothelial permeability to macromolecules occur in the aorta; a fraction of them are associated with dividing cells. Hotspots occur particularly frequently downstream of branch points, where lesions develop in young rabbits and children. However, the pattern of lesions varies with age, and can be explained by similar variation in the pattern of macromolecule uptake. We investigated whether patterns of hotspots and mitosis also change with age. MethodsEvans’ Blue dye-labeled albumin was injected intravenously into immature or mature rabbits and its subsequent distribution in the aortic wall around intercostal branch ostia examined by confocal microscopy and automated image analysis. Mitosis was detected by immunofluorescence after adding 5-bromo-2-deoxiuridine to drinking water. ResultsHotspots were most frequent downstream of branches in immature rabbits, but a novel distribution was observed in mature rabbits. Neither pattern was explained by mitosis. Hotspot uptake correlated spatially with the much greater non-hotspot uptake (p < 0.05), and the same pattern was seen when only the largest hotspots were considered. ConclusionsThe pattern of hotspots changes with age. The data are consistent with there being a continuum of local permeabilities rather than two distinct mechanisms. The distribution of the dye, which binds to elastin and collagen, was similar to that of non-binding tracers and to lesions apart from a paucity at the lateral margins of branches that can be explained by lower levels of fibrous proteins in those regions.
Highlights
Elevated uptake of circulating macromolecules, low density lipoprotein (LDL), by the arterial wall is seen in anatomical locations that are susceptible to atherosclerosis and is thought to be a risk factor for it
The hypothesis is consistent with earlier observations that mitosis rates are higher in areas of Evans’ Blue dye-albumin (EBA) uptake by the pig aortic wall [9]
The present study investigated the hypothesis that patterns of EBA hotspots and mitosis change with age in rabbits in the same way as lesions, and examined the proportion of total uptake that occurs via hotspots
Summary
Elevated uptake of circulating macromolecules, low density lipoprotein (LDL), by the arterial wall is seen in anatomical locations that are susceptible to atherosclerosis and is thought to be a risk factor for it. The cell turnover leaky junction hypothesis of Weinbaum et al [7] proposes that intercellular junctions temporarily widen when endothelial cells divide or die, leading to foci of high permeability for macromolecules such as LDL. Typical dimensions of these leaky junctions were estimated by Chen et al [8] to be 80e1330 nm during mitosis and 15e1000 nm for dead or dying cells. The hypothesis is consistent with earlier observations that mitosis rates are higher in areas of Evans’ Blue dye-albumin (EBA) uptake by the pig aortic wall [9]. The distribution of the dye, which binds to elastin and collagen, was similar to that of non-binding tracers and to lesions apart from a paucity at the lateral margins of branches that can be explained by lower levels of fibrous proteins in those regions
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