Atherosclerosis is the hardening and narrowing of arteries caused by the gradual accumulation of fatty deposits, known as plaque, within the vessel walls. This disease is the foundational pathology for most cardiovascular events, including heart attacks and strokes. Plaque development is a slow biological cascade involving distinct cellular and molecular processes over many years.
Endothelial Dysfunction: The Initial Damage
Atherosclerosis begins with a malfunction of the endothelium, the single-cell layer that lines the inside of every artery and normally maintains a smooth, healthy vessel environment. This delicate lining can become damaged or dysfunctional due to persistent exposure to risk factors such as high blood pressure, elevated cholesterol levels, smoking, and diabetes. Endothelial dysfunction is characterized by a reduction in the production of nitric oxide, a molecule that typically signals the artery to relax and expand.
The loss of this protective function causes the endothelial cells to become both permeable and “sticky,” shifting the vessel wall from an anti-inflammatory to a pro-inflammatory state. This altered state allows low-density lipoprotein (LDL) cholesterol particles circulating in the blood to infiltrate the sub-endothelial space. This sets the stage for the body’s immune response and the subsequent stages of plaque formation.
The Accumulation of Lipids: Forming the Fatty Streak
Once LDL cholesterol enters the arterial wall, it is often modified through oxidation, which makes the particles highly inflammatory. The dysfunctional endothelium expresses adhesion molecules that attract circulating monocytes to the site of injury. These monocytes then migrate into the arterial wall, where they differentiate into macrophages.
The macrophages attempt to clear the modified LDL particles by ingesting them through specialized scavenger receptors. This process is unregulated, leading the macrophages to gorge on the lipids until they become engorged and acquire a characteristic foamy appearance. The clustering of these lipid-laden macrophages, known as foam cells, forms the earliest visible lesion in the artery, called the fatty streak. This initial lesion is relatively flat and does not significantly impede blood flow, and is potentially reversible with risk factor modification.
Maturation and Hardening: Developing the Fibrous Plaque
The fatty streak evolves into a more complex and advanced lesion, known as the fibrous plaque, through a sustained inflammatory process. Smooth muscle cells (SMCs) from the underlying layer of the artery, the media, begin to migrate into the intima and proliferate. These SMCs then produce large amounts of extracellular matrix, predominantly collagen, which forms a dense, protective layer—the fibrous cap—over the lipid and foam cell core.
The growth of the fibrous cap causes the plaque to expand and physically narrow the artery, a condition known as stenosis. As the plaque matures, calcium deposits accumulate, hardening the plaque and reducing the flexibility of the arterial wall. Plaques are categorized by the thickness of their cap and the size of the underlying lipid pool: stable plaques have a thick cap and smaller core, while unstable lesions have a thin cap and a large, soft lipid core.
Plaque Rupture and Acute Clinical Events
The advanced atherosclerotic plaque poses a risk not primarily through chronic narrowing but through its potential to suddenly destabilize and rupture. This acute event occurs when the thin fibrous cap of a vulnerable plaque becomes inflamed and weakened, often due to persistent macrophage activity that degrades the collagen matrix. Mechanical stress from blood flow can then cause the cap to tear or fissure.
When the cap ruptures, the highly pro-coagulant material from the plaque’s lipid core is immediately exposed to the bloodstream. The blood recognizes this material as a severe injury and triggers the coagulation cascade, resulting in the rapid formation of a blood clot, or thrombus, at the site of the rupture. This sudden thrombus can quickly grow large enough to completely block the flow of blood through the artery. If this occurs in a coronary artery, it causes a myocardial infarction; if it occurs in an artery leading to the brain, it results in an ischemic stroke.