Diabetologia (1997) 40: S108–S110

 Springer-Verlag 1997

The pathogenesis of

R.G. Gerrity, A.S. Antonov Department of Pathology, Medical College of Georgia, Augusta, Georgia, USA

Atherosclerosis is the underlying cause of arterial oc- sequence of plaque types and plaque composition, is clusion resulting in myocardial and cerebral infarc- different in diabetic patients, only that the progression tion, and is the leading cause of death in Western Eu- of the disease is grossly accelerated. If this is the case, rope and the United States [1]. It is estimated that in one approach to the problem is to identify factors and the United States alone, about six million persons mechanisms in diabetic conditions which accelerate have symptomatic myocardial ischaemia, and that ap- the atherogenic mechanisms known to occur in non- proximately one American dies every minute because diabetic states. However, this approach as been ham- of atherosclerotic coronary disease. Further- pered by the lack of good humanoid animal models of more, atherosclerosis is the major complication of dia- diabetic atherosclerosis. betes mellitus, and several studies indicate that dia- The lesions of atherosclerosis, or plaques, have gen- betic patients have 2–5 times the death rate due to ath- erally been classified in three categories: the fatty erosclerotic disease than non-diabetic patients [2]. streak, the fibrous plaque, and the complicated lesion The relative risk of peripheral in dia- [3, 4]. Of these lesion types, the fatty streak is the earli- betic patients is even greater. In the past two decades, est to be seen in both humans and hyperlipaemic ani- atherosclerosis has been the subject of intense study mal models. In humans, it is common in pre-teenage into both its causative (risk) factors as well as the children, and by age 30 years, up to 30– 50% of the aor- pathobiology of the lesions. Although epidemiologi- tic intimal surface may be covered by fatty streak le- cally derived risk factors can be statistically correlated sions. Fatty streaks are grossly flat, lipid-rich lesions with clinical disease, it has proven difficult to correlate consisting predominantly of lipid-laden them with lesion pathology.The extremely long course and minimal numbers of smooth muscle cells. The of the disease prior to clinical significance, together high lipid content of these lesions gives them a typical with the impossibility of sequentially sampling human yellowish colour on gross examination. Such lesions specimens, has made it difficult to conclusively iden- do not occlude the lumen, and thereforedo not present tify the sequence of human plaque development. As a clinical symptoms. In contrast, the fibrous plaque is result, much of our understanding of the cellular representative of various forms of advanced athero- pathobiology of atherosclerosis has been obtained sclerosis and is widely accepted as the most common from animal models and from tissue culture of cells atherosclerotic precursor to occlusive lesions. As isolated from the arterial wall and blood. Although such, it is the major determinant of clinically signifi- no single animal model reproduces the human disease cant disease. This lesion is whitish in gross appearance exactly, such models have been invaluable in further- and protrudes into the vessel lumen. Its distribution is ing our understanding of the cellular composition, bio- more focal in nature than that of fatty streaks. Histo- chemistry, localization and structure of plaques. The logically, fibrous plaques consist of layers of initial pathogenesis of diabetic atherosclerosis is even more smooth muscle cells, many of which are lipid-laden, poorly understood. There is no evidence to suggest surrounded by collagen fibrils and elastin fragments that the pathomorphology of the disease, that is, the in a proteoglycan-rich matrix forming a “fibrous cap” overlying a core of lipid-laden macrophages, extracel- lular lipid and necrotic cellular debris. Early fatty Corresponding author: Dr. R.G. Gerrity, Department of Pa- thology, Medical College of Georgia, Augusta, GA 30912– streaks do regress, but fibrous plaques in older age are 3605, USA found at the same anatomical locations as these early Abbreviations: PDGF, derived growth factor; LDL, fatty streaks, particularly in the coronary and extracra- low density nial cerebral . R.G. Gerrity, A.S. Antonov: The pathogenesis of atherosclerosis S109

Virtually all occlusive lesions are of the third type, endothelial integrity, beginning after only a few the complicated lesion, resulting from necrosis, calci- weeks of hyperlipaemia, and at times concurrent fication, and mural of fibrous plaques. Al- with the accumulation of LDL in the intima [12]. Re- though there is good evidence that fibrous plaques cruitment of monocytes into these lesion-susceptible are complicated by these phenomena, and that pla- sites is mediated by the production of chemotactic que rupture and thrombosis may occur episodically, factors in these areas which are induced in hyperlip- thus adding to plaque volume and occlusion, the rela- aemia [14]. More recent studies have also identified tionship between fatty streaks and fibrous plaques re- an array of endothelial adhesion molecules which mains less clear and a matter of controversy. More re- are actively involved in the initial adhesion of mono- cently, McGill [3] and others have proposed the exis- cytes and other leukocytes to the endothelial lining tence of a transitional lesion which may be the link [15]. Both monocyte chemotactic factors and adhe- between the fatty streak and the fibrous plaque. sion molecules have been shown to be inducible on Grossly, these lesions resemble fatty streaks, but mi- endothelial cells in culture by oxidized and modified croscopically contain a core of necrotic debris and ex- LDL [16]. tracellular lipid not seen in the fatty streak, thus dis- Intimal monocytes thus recruited into the vessel playing morphological characteristics of both fatty wall are rapidly transformed into lipid-laden mac- streak and fibrous plaque. Chronologically, these le- rophage foam cells by the unregulated uptake of sions occur predominantly in 20–30-year-old males, modified via the scavenger and oxidized at sites where fatty streaks are found in younger LDL receptor pathways [17, 18]. Their increase in men, and fibrous plaques are found in older males size as they accumulate lipid is the major contributor [3]. If this is correct, then the transitional lesion may to increased lesion volume during the development represent a relatively short-lived lesion transitional of fatty lesions. There is evidence from the swine between fatty streaks and fibrous plaques. model that large numbers of macrophages migrate The events involved in the progression of athero- back through the into the blood and sclerosis from fatty streak to fibrous plaque to clini- are cleared by the reticuloendothelial system, partic- cally significant atherosclerosis may never be eluci- ularly at the fatty streak stage [6]. The monocyte dated with certainty in humans. However, as stated may thus serve as an early defence mechanism to above, analysis of this sequence in humanoid animal clear excess lipid from the lesion. However, it is clear models [4–9] of atherosclerosis has proven to be par- that as lesions progress, necrosis contributes ticularly useful, and in many instances, identical or to the lipid core of the plaque [19]. There is evidence similar counterparts have been found in human ves- from both non-human primate and swine models sels derived from both surgically removed and au- that endothelial cell damage and retraction occur at topsy material. It is now universally accepted that ar- sites where foam cells migrate or are in close proxim- eas of predilection to atherosclerosis exist in the ar- ity to the endothelium, and that these serve as foci for teries of both man and experimental animals, and platelet adherence [5–8]. Endothelial cell damage at that this predilection, or susceptibility, results from these sites may be associated with excessive stretch- functional differences in the vessel wall at these sites, ing of the endothelium by plaque growth, enhanced possibly induced by haemodynamic conditions [10]. membrane fragility due to altered lipid composition, Such lesion-susceptible areas have been studied ex- release of lytic enzymes by macrophages, or toxicity tensively in swine [4–6, 10] and pigeon [11] models, due to oxidation of intimal lipoproteins by the macro- and recent studies have shown them to exist in human phages themselves [18]. Although the ability of mac- arteries. Systematic studies of lesion-susceptible rophages to actively oxidize lipids may be a mecha- areas in animal models shows that these areas have nism whereby they enhance lipoprotein uptake, it is characteristics of enhanced endothelial permeability also clear that lipoproteins oxidized by macrophages and intimal accumulation of blood macromolecules are toxic to endothelial and smooth muscle cells, and even in normal animals [10]. In conditions of hyper- as such, macrophages may contribute to the necrotic lipaemia, the earliest detectable event is a preferen- processes within the plaque. Furthermore, activated tial enhanced uptake and accumulation of athero- macrophages have been shown to secrete growth fac- genic low-density lipoprotein (LDL) across an intact tors for smooth muscle cells [9], including a mitogen endothelium [12], probably through a mechanism of similar to platelet derived growth factor (PDGF). Mi- increased bulk phase vesicular transport [10]. Similar togens released by macrophages and by ad- accumulation of LDL has been shown in arteries herent to sites of endothelial damage or retraction from young humans [13]. may induce proliferation of smooth muscle cells in In these lesion-susceptible areas, the earliest dis- the intima derived from either pre-existing intimal cernible cellular event in atherogenesis is the adhe- cell masses or from smooth muscle cells which have sion of blood monocytes to the endothelium, and migrated from the media. PDGF may also take their migration into the intima through endothelial part in this latter process, as it is known to be chemo- junctions [5–8]. This occurs without disruption of tactic for smooth muscle cells. Smooth muscle cell S110 R.G. Gerrity, A.S. Antonov: The pathogenesis of atherosclerosis proliferation may occur at different stages in differ- 2. Steiner G (1995) Diabetes and atherosclerosis: epidemiol- ent plaques, depending upon geographic site, the ex- ogy and intervention trials. In: Woodford FP, Davignon J, istence of intimal smooth muscle cell masses, or the Sniderman A (eds) Artherosclerosis X. Elsevier, Amster- dam, pp 749–752 proximity of medial cells to the intima. Regardless, 3. McGill HC Jr (1990) Questions about the natural history of these cells form a fibrous cap over the lipid core of human atherosclerosis. In: Glagov S, Newman WP III, the lesion and add to plaque growth and progression Schaffer SA (eds) Pathobiology of the human athero- by increased production of collagen, elastin, and ma- sclerotic plaque. Springer, Berlin Heidelberg New York, trix components. The trapping of lipid-laden foam pp 1–11 cells beneath the fibrous cap leads to their necrosis, 4. Gerrity RG (1989) Morphological development of the ath- erosclerotic plaque. In: Subbiah MTR (ed) Atherosclero- contributing to the mass of extracellular lipid in the sis: a pediatric perspective. CRC Press, Boca Raton, pp 9– core of the lesion [19]. Protrusion of the plaque into 30 the lumen, together with increased fragility of endo- 5. Gerrity RG (1981) The role of the monocyte in atherogen- thelial cell membranes may also result in episodic esis. I. Transition of blood-borne monocytes into foam cells plaque rupture or endothelial denudation resulting in fatty lesions. Am J Pathol 103: 181–190 in focal fibrin-platelet thrombi which may become in- 6. Gerrity RG (1981) The role of the monocyte in atherogen- corporated into the plaque, increasing plaque vol- esis. II. Migration of foam cells from atherosclerotic le- sions. Am J Pathol 103: 191–200 ume. Growth of the fibrous plaque by cell prolifera- 7. Faggiotto A, Ross R, Harker L (1984) Studies of hypercho- tion, connective tissue synthesis and complicating se- lesterolemia in the nonhuman primate. I. Changes that lead quelae of rupture and thrombosis ultimately result in to fatty streak formation. 4: 323–340 clinically significant occlusion. 8. Faggiotto A, Ross R (1984) Studies of hypercholesterol- It is now accepted that these events occur in the emia in the nonhuman primate. II. Fatty streak conversion atherogenic sequence, and that some are manifest ear- to fibrous plaque. Arteriosclerosis 4: 341–356 9. Ross R (1986) The pathogenesis of atherosclerosis – an up- lier than others, at least in animal models. For instance, date. N Engl J Med 314: 488–500 enhanced LDL deposition and monocyte recruitment 10. Gerrity RG (1990) Arterial endothelial structure and per- can be detected even at short durations of hyperlipida- meability as it relates to susceptibility to atherogenesis. In: emia. 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Arch Pathol Lab Med 108: 817–822 monocytes, macrophages, and smooth muscle cells all 13. Hoff HF (1976) Apolipoprotein localization in human cra- nial arteries, coronary arteries and the aorta. Stroke 7: undergo structural and functional changes at various 390–393 stages, and all play a role in atherogenesis, our under- 14. Gerrity RG, Goss JA, Soby L (1985) Control of monocyte standing of the in vivo interactions among the three recruitment by chemotactic factor(s) in lesion-prone areas cell types is incomplete. Recent research has focused of swine aorta. Artenosclerosis 5: 55−66 on the molecular mechanisms controlling the interac- 15. Pober JS, Cotran RS (1990) Cytokine-endothelial interac- tions among the three cell types, and elucidation of tions in , immunity, and vascular injury. J Am Soc Nephrol 1: 225–235 such interactions is key to our understanding of the 16. Cushing SD, Berliner JA, Valente AJ, et al. (1990) Mini- atherogenic sequence. Also critical to our understand- mally modified low density lipoprotein induces monocyte ing of atherogenesis is how risk factors linked to an in- chemotactic protein 1 in human endothelial cells and creased incidence of atherosclerosis are translated at smooth muscle cells. Proc Natl Acad Sci USA 87: 5134– cellular and molecular levels to initiate or augment 5138 the mechanisms described. This knowledge is funda- 17. Mahley RW, Innerarity TL (1983) Lipoprotein receptors and homeostasis. Biochim Biophys Acta 737: mental to the development of new approaches to in- 197−222 tervention and prevention, as well as novel tools for 18. Steinberg D (1995) The oxidative modification hypothesis early diagnosis. of atherogenesis: strengths and weaknesses. In: Woodford FP, Davignon J, Sniderman A (eds) Atherosclerosis X. Elsevier, Amsterdam, pp 25–29 References 19. Stary HC (1990) Changes in the cells of atherosclerotic le- sions as advanced lesions evolve in coronary arteries of 1. 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