Elsevier

Medical Hypotheses

Volume 79, Issue 4, October 2012, Pages 535-538
Medical Hypotheses

Critical sequences of phenomena in the progression of atherosclerotic lesions, with reference to the role of microvessels

https://doi.org/10.1016/j.mehy.2012.07.013Get rights and content

Abstract

Atherosclerosis affects the inner layers of human arteries, and causes major problems by blocking, directly or indirectly, the flow of blood. This paper concerns the growth of atherosclerotic lesions (atherogenesis), in particular potential factors that may allow a form of ‘positive feedback’ that drives the development of lesions, and considers the role of microvessels. The lesions of atherosclerosis have previously been compared to, or thought of as, sites of inflammation, and involve the accumulation of cells, including large lipid-containing macrophages, and extracellular elements. In tissues other than arteries inflammation may involve, amongst other phenomena, a resolution stage with the removal or departure of macrophages via lymphatics. However, the inner aspects of large arteries do not normally demonstrate lymphatics or other microvessels, and there is evidence from animal work that the lack of vessels effectively contributes to the development of atherosclerosis, as this limits the egress of macrophages and other elements. Conversely, in humans microvessels have been suggested to play a key role in the progress of atherosclerotic lesions. The importance of microvessels is herein considered, in particular the potentially paradoxical situation where as stated the lack of microvessels can be considered to allow atherosclerosis, but on the other hand these structures are involved in lesion development – the explanation can be seen to relate to the relatively short length of time which is assessable in animal models, compared to the lengthy period over which lesions appear to develop in humans. In addition, consideration is given to other factors, including haemodynamic factors related to the physical presence of lesions, which could lead to phenomena that can be regarded as a vicious cycle of events that lead to growth of the lesion. Specifically initial inflammation may lead to scarring and anatomical distortion, which through haemodynamic and physical factors leads to more damage, more inflammation and scarring, and so on.

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.

References (43)

  • S. Standring

    Gray’s anatomy

    (2008)
  • K. Skalen et al.

    Subendothelial retention of athreogenic lipoproteins in early atherosclerosis

    Nature

    (2002)
  • R.G. Gerrity et al.

    Dietary induced atherogenesis in swine

    Am J Pathol

    (1979)
  • T. Watanabe et al.

    Role of macrophages in atherosclerosis

    Lab Invest

    (1985)
  • J.C. Lewis et al.

    Endothelial surface characteristics in pigeon coronary artery atherosclerosis

    Lab Invest

    (1982)
  • I. Joris et al.

    Studies on the pathogenesis of atherosclerosis: I. Adhesion and emigration of mononuclear cells in the aorta of hypercholesterolemic rats

    Am J Pathol

    (1983)
  • G.J. Randolph

    Emigration of monocyte derived cells to lymph nodes during resolution of inflammation and its failure in atherosclerosis

    Curr Opin Lipidol

    (2008)
  • G. Dai et al.

    Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature

    Proc Natl Acad Sci USA

    (2004)
  • F. Helderman et al.

    Effect of shear stress on vascular inflammation and plaque development

    Curr Opin Lipidol

    (2007)
  • H. Hahn et al.

    The role of cellular adaptation to mechanical forces in atherosclerosis

    Arterioscler Thromb Vasc Biol

    (2008)
  • N.M. Aqel et al.

    Identification of macrophages and smoth muscle cells in human atherosclerosisis using monoclonal antibodies

    J Pathol

    (1985)
  • Cited by (2)

    View full text