Experiments on cultured cells and animals now indicate that the trouble begins when LDLs from the blood collect in the intima, the part of the arterial wall closest to the bloodstream. At reasonable concentrations in the blood, LDLs can pass in and out of the intima, which consists mainly of the endothelial cells that line vessel walls, the underlying extracellular matrix (connective tissue), and a smattering of smooth muscle cells (matrix producers). But in excess, LDLs tend to become stuck in the matrix.
As the LDLs accumulate, their lipids undergo oxidation (similar to the processes that rust pipes and spoil butter) and their proteins undergo both oxidation and glycation (binding by sugars). Cells in the vessel wall seem to interpret the changes as a danger sign, and they call for reinforcements from the body’s defense system.
In particular, endothelial cells display adhesion molecules on their blood-facing surface. These molecules latch like Velcro onto quiescent inflammatory cells known as monocytes, which normally circulate in the blood. This interaction causes the cells to drop from the circulation and to roll along and attach to the artery wall. The modified LDLs also spur the endothelial cells and smooth muscle cells of the intima to secrete chemicals called chemokines, which attract monocytes. Much as hounds track the scent of their prey, the monocytes squeeze between endothelial cells and follow the chemical trail to the intima.
Chemokines and other substances elaborated by the endothelial and smooth muscle cells then induce the monocytes to multiply and mature into active macrophages: fully armed warriors, ready to unleash their various weapons against the body’s enemies. These warriors also set about clearing perceived invaders from the vessel wall. Reacting to proteins emitted by stimulated endothelial and intimal smooth muscle cells, the macrophages decorate their surface with molecules called scavenger receptors, which capture modified LDL particles and help the macrophages ingest them. The macrophages ultimately become so packed with fatty droplets that they look foamy when viewed under a microscope. Indeed, pathologists refer to the fat-filled macrophages as foam cells.
Just as monocytes follow adhesion molecules and chemokines into the intima, so do T lymphocytes, white blood cells that represent a different branch of the immune system. These lymphocytes also release cytokines that amplify inflammatory activities in artery walls. Together the foamy macrophages and a lesser number of T lymphocytes compose the so-called fatty streak, a precursor of the complex plaques that later disfigure arteries. Disturbingly, many Americans harbor nascent plaques as early as their teens.
Fueling Plaque Growth
WHEN AN INFLAMMATORY response in, say, a scraped knee successfully blocks an infection, macrophages release molecules that facilitate healing. A “healing” process also accompanies the more chronic, low-level kind of inflammation that operates in atherosclerosis. Instead of restoring artery walls to their original state, though, the process perversely remodels— changes the character of—the wall, eventually generating a bigger, more complicated plaque.
In recent years, biologists have learned that macrophages, endothelial cells and smooth muscle cells of the inflamed intima secrete factors that prod smooth muscle cells of the media (the tissue under the intima) to migrate to the top of the intima, replicate and synthesize components of the extracellular matrix. The cells and matrix molecules coalesce into a fibrous covering overlying the original atherosclerotic zone. As this “cap” matures, the zone underneath generally changes somewhat. Most obviously, some fraction of the foam cells die, releasing lipids. For this reason, pathologists denote the region under the cap as the lipid or necrotic core.