Monocytes and Susceptibility to Atherosclerosis

In recent years, it has become increasingly clear that atherosclerotic lesions do not occur randomly in the arterial system. Rather, they have been shown to favor certain regions, while sparing others, both in the human (McGill, 1968a; McGill, 1968b; Mitchell and Schwartz, 1965) and in experimental models (Faggiotto and Ross, 1984; Gerrity et al., 1979; Jerome and Lewis, 1985; Joris et al., 1983). Modern computer-assisted image processing techniques have been developed to express the topographic distribution of lesions in statistical terms, thus quantifying precisely previous qualitative studies which have indicated that inflow tracts of ostia and flow dividers are particularly susceptible to early lesion development (Cornhill et al., 1985). Other studies have clarified the cellular composition of atherosclerotic plaques in both man (Geer et al., 1961; Ross et al., 1984) and animal models (Faggiotto and Ross, 1984; Gerrity et al., 1979, Jerome and Lewis, 1985; Joris et al., 1983; Faggiotto et al., 1984; Gerrity, 1981a; Gerrity, 1981b; Jerome and Lewis, 1984; Wissler and Vesselinovitch, 1977), and have provided insight into the relationships between cellular composition and lesion type, location, and progression. The fatty streak lesion (the earliest detectable form of atherosclerosis in man), is characteristically a lipid-rich, flat lesion consisting predominantly of macrophage foam cells with minimal smooth muscle cell involvement (McGill, 1968a). Advanced atherosclerosis in older individuals is more typified by various forms of fibrous plaques dominated by smooth muscle cells and enhanced amounts of connective tissue protein and matrix. The central core of such lesions consists of both intra- and extra-cellular lipid accumulations covered on the luminal aspect by a fibrous cap of smooth muscle and connective tissue. The question of whether the fatty streak is a precursor to the fibrous plaque has long been debated. However, recent data, reviewed by McGill (1968) supports the precursor concept, in that increased surface area coverage by fatty streaking precedes advanced plaques in coronary arteries. Stary (1985) has also shown that lesions in young children consist predominantly of macrophage-derived foam cells, with a few underlying lipid-laden smooth muscle cells. However, he also demonstrated advanced fibrous plaques at the same anatomical sites in older individuals, confirming earlier data (Geer et al., 1961; Robertson et al., 1963) which indicated an age-dependent relationship between fatty streaks and fibrous plaques at the same anatomical site. If, as these data would suggest, the fatty streak is indeed the precursor of the clinically-significant fibrous plaque, then the mechanisms controlling monocyte involvement in fatty streak initiation are of considerable importance, since the monocyte-derived foam cell is the predominant cell of the fatty streak. Furthermore, it has been demonstrated that one of the earliest events to occur in such lesion-susceptible areas is the large-scale recruitment of blood monocytes into the intima (Faggiotto and Ross, 1984; Gerrity et al., 1981a,b; Jerome and Lewis, 1985; Joris et al., 1983; Jerome and Lewis, 1984; Robertson et al., 1963).