Critical sequences of phenomena in the progression of atherosclerotic lesions, with reference to the role of microvessels
Introduction
Atherosclerosis is a condition that affects selected sites in the arterial system, e.g. in the coronary arteries, the carotids, the aorta, or the arteries of the lower limbs. The development of atherosclerotic lesions is termed atherogenesis. Significant lesions are associated with hyperlipidaemia. The exact initiating event(s) for atherosclerosis is unclear, but may involve binding of an excessive/aberrant lipid or lipid-containing structure to normal components of the inner aspects of arteries. There is formation of foam cells (cells filled with lipids) and collagen deposition within the relevant sites. Lesions have been labelled as atherosclerotic plaques (also known as atheromatous plaques) [1], [2]. Initially atherosclerosis affects the inner aspects of arteries, and later the changes may extend more deeply, toward the media. The plaques may impinge upon the lumen of the vessel and cause a stenosis, and/or may lead to overlying thrombosis. Because of these and other complications, atherosclerosis is a major cause of morbidity and mortality in the Western world.
This article is intended to assess the relevance of microvessels, including lymphatic vessels, in this condition. There is some potentially conflicting evidence regarding these to be described; on the one hand, there is evidence that lack of microvessels allows atherosclerosis to develop, and, on the other hand, there is evidence that the presence of microvessels contributes to the development of lesions and their complications. In addition, different phenomena will be integrated into a description of key events that allow a unifying hypothesis of how clinically significant lesions grow, and in particular how lesions, once initiated, may be self-promoting.
Section snippets
Normal anatomy/microanatomy of arteries
Normal arteries have different layers [3]. Starting from the inner/luminal aspect, there is a layer of endothelium overlying loose connective tissue known as the intima. The thickness of the intima may increase through life. On the outside of the intima is a relatively thick layer of typically closely packed smooth muscle cells, this layer being called the media. On the outer aspect of the arteries is further loose connective tissue – this area is called the adventitia. Microvessels are not
Relevant studies of atherogenesis in animals or in vitro, and factors contributing to the development of atherosclerotic lesions
Proteins that normally bind to lipids in the circulation are termed apolipoproteins, and there are various types of these, e.g. one termed apolipoprotein B. An early event in atherosclerosis appears to be the accumulation of apolipoprotein B, via binding to vascular proteoglycans, based on studies in transgenic mice [6]. Other studies in relevant animal models have shown that another early phenomenon in atherogenesis is the adhesion of circulating monocytes to the endothelium of the arterial
Atherosclerotic plaques and the mechanisms by which they become clinically apparent
Atherosclerotic plaques in humans appear macroscopically as thickened/raised lesions, which may be pale due to accumulation of connective tissue elements such as collagen. What the microanatomical features may be of early human plaques or their forerunner lesions are not currently well-defined, but features at the time plaques become evident include a fibrous cap, macrophage foam cells, as well as extracellular lipid, cholesterol crystals, T lymphocytes, mast cells, and necrotic material [18],
Comparison of atherosclerosis to inflammation, and relevant physiology and events in inflammation outside of arteries, notably relating to lymphatics
For various reasons, including the presence of leukocytes and the fibrosis, the lesions are considered to represent, or at least involve to a very significant degree, an inflammatory process [31], [32]. It is thought that, as post-capillary venular endothelium does in extra-arterial inflammation [33], arterial endothelium could play an important role in directing leukocyte migration from the arterial lumen, by expressing adhesion molecules such as VCAM-1 and ICAM-1 [34], [35].
To continue the
Hypothesis
There seems to be ostensibly conflicting findings in that in the animal models described microvessels are not a feature of atherosclerotic lesions, including plaque-like lesions [10], and their absence has been given as a factor in the development of lesion, whereas in humans microvessels may be seen in lesions and have been considered to contribute to the progress of lesions. Atherosclerosis should necessarily be seen as, rather than an event, a process, in humans involving a sequence of
Evaluation of the hypothesis, and review of key evidence
The animal models described were assessed for what can be seen as a relatively short period of time. Relevant animal studies [7], [8], [9], [10] were done over a period of months or a year. It has been suggested that lack of microvessels in arteries, based on animal studies, effectively allows atherosclerosis, and in relation to this Randolph has highlighted ‘specialized anatomical features of the artery’ [11]. Human lesions appear to take much longer to develop [1], [2], and typically present
Conclusion
Atherosclerotic lesions are a major cause of clinical problems. They are associated with hyperlipidaemia, and there is inner arterial accumulation of lipids and inflammatory cells. While this accumulation of these materials has been compared to inflammation an extra-arterial setting, it could in theory be relatively easily be cleared/resolved outside of arteries. However, in the inner arterial setting, at least in the initial stages while the lesion is being established, a lack of microvessels
Conflict of interest statement
None declared.
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