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Activation of endothelial cells causes a monocyte recruitment cascade involving rolling, adhesion, activation and transendothelial migration (Figure 1). Selectins, especially P-selectin, mediate the initial rolling interaction of monocytes with the endothelium (32). Monocyte adherence is then promoted by endothelial cell immunoglobulin-G proteins including VCAM-1 and ICAM-1 (32). Potent chemoattractant factors such as MCP-1 and IL-8 then induce migration of monocytes into the subendothelial space (33-35). Ly6^hi monocytes, versus Ly6^lo, preferentially migrate into the subendothelial space to convert to proinflammatory macrophages in mice (36-38). The enhanced migration of Ly6^hi versus Ly6^lo monocytes likely results from increased expression of functional P-selectin glycoprotein ligand-1 (39). In addition, the number of blood monocytes originating from the bone marrow and spleen, especially Ly6^hi cells, increases in response to hypercholesterolemia (36). Furthermore, hypercholesterolemia and atherosclerosis increase monocytosis in humans (40,41). Importantly, increased numbers of inflammatory CD14⁺⁺ CD16⁺ monocytes independently predicted cardiovascular death, myocardial infarction, and stroke in patients undergoing elective coronary angiography (42). Intimal macrophages also result from proliferation of monocyte/macrophages, especially in more advanced lesions (43). During the initial fatty streak phase of atherosclerosis (Figure 1), the monocyte-derived macrophages internalize the retained apoB-containing lipoproteins, which are degraded in lysosomes, where excess free cholesterol is trafficked to the endoplasmic reticulum (ER) to be esterified by acyl CoA: cholesterol acyltransferase (ACAT), and the resulting cholesteryl ester (CE) is packaged into cytoplasmic lipid droplets, which are characteristic of foam cells (42) (Figure 2) (44,45). Modification of apoB lipoproteins via oxidation and glycation enhances their uptake through a number of receptors not down-regulated by cholesterol including CD36, scavenger receptor A, and lectin-like receptor family (see details below) (Figure 2) (46,47). Enzyme-mediated aggregation of apoB lipoproteins enhances uptake via phagocytosis (Figure 2) (48,49). In addition, native remnant lipoproteins can induce foam cell formation via a number of apoE receptors (LRP1 and VLDLR) (Figure 2) (50,51). Uptake of native LDL by fluid phase pinocytosis may also contribute to foam cell formation (Figure 2) (52,53).

Macrophage Cholesterol Metabolism. Native LDL is recognized by the LDL receptor (LDLR). The LDL is endocytosed and trafficked to lysosomes, where the cholesteryl ester (CE) is hydrolyzed to free cholesterol (FC) by the acid lipase. The FC is transported to the endoplasmic reticulum (ER) to be esterified by acyl CoA: cholesterol acyltransferase (ACAT). Increased FC in an ER regulatory pool initiates a signaling cascade resulting in down-regulation of the LDL receptor. Cholesterol regulation of the LDLR prevents foam cell formation via this receptor in the setting of hypercholesterolemia. ApoB containing lipoproteins that also contain apoE (apoE remnants, VLDL) can cause cholesterol accumulation via interaction of apoE with apoE receptors including the LRP1 and the VLDL receptor, which are not regulated by cellular cholesterol. Uptake of native LDL by fluid phase pinocytosis may also contribute to foam cell formation.