Atherosclerosis is a complex multi-stage disease of the vasculature and begins with damage to the endothelial vessel lining. Vascular endothelial cells respond to the damage by upregulating lumenal adhesion proteins, inflammatory mediators, and oxidative enzymes. Immune cells adhere to the activated endothelium and extravasate to the intima where they expand the inflammatory response. Lipoprotein particles are targeted by oxidative enzymes to generate pathogenic oxidized LDL. Macrophages within the intimal layer then phagocytose and accumulate oxLDL, promoting their development into foam cells. Foam cells accumulate and give rise to fatty streaks within the vessel wall.
Vascular smooth muscle cells proliferate, migrate, and secrete matrix proteoglycans to form a protective fibrous cap around the plaque. They undergo partial transdifferentiation and adopt a bone cell-like phenotype. This leads to vessel wall calcification and loss of arterial elasticitiy. Intimal-medial layer thickening (IMT) of the artery is indicative of atherosclerosis progression. In addition, local upregulation of angiogenic factors induces neoangiogenesis to supply blood to the growing plaque.
Foam cell death and lack of dead cell clearance result in the formation of a necrotic core within the plaque. Increased protease expression by both stromal and immune cells progressively weakens the fibrous cap. Fibrous cap thinning eventually leads to plaque rupture into the arterial lumen with direct exposure of the blood to the necrotic core. This triggers rapid thrombosis in the arterial lumen, blockage of blood flow (stenosis), and possible stroke or myocardial infarction. Alternatively, weakening of the arterial vessel wall contributes to aneurysm formation and potential bleeding into the extravascular space. The development of atherosclerosis is accelerated by a high fat diet, smoking, age, hypertension, and genetic mutations in molecules involved in normal vascular biology.