Question
Pathogenesis of Atherosclerosis
Answer
Atherosclerosis is best explained by the “response to injury” hypothesis, in which the atherosclerotic plaque is a chronic inflammatory and healing response of the arterial wall to endothelial injury:
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Chronic endothelial injury: Caused by risk factors such as hyperlipidaemia (especially elevated LDL), hypertension, smoking, toxins, homocysteine, and haemodynamic stress (turbulent flow at vessel branch points). This results in endothelial dysfunction — increased permeability and adhesiveness.
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Lipoprotein entry and modification: LDL accumulates in the intima and undergoes oxidation and other modifications, becoming pro-inflammatory and cytotoxic.
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Monocyte adhesion and migration: Dysfunctional endothelium expresses adhesion molecules (VCAM-1) that recruit circulating monocytes, which migrate into the intima and transform into macrophages.
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Foam cell formation: Macrophages phagocytose oxidized LDL via scavenger receptors, becoming lipid-laden “foam cells” — the hallmark of the earliest lesion, the fatty streak.
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Smooth muscle cell recruitment: Growth factors (PDGF, FGF, TGF-α) released by activated platelets, macrophages, and the endothelium stimulate smooth muscle cell migration from the media into the intima, along with their proliferation and extracellular matrix (collagen) synthesis.
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Fibrous cap and lipid core formation: The proliferating smooth muscle cells and deposited collagen form a fibrous cap over a core of lipid and necrotic/apoptotic foam cell debris — forming the mature atheromatous (fibrofatty) plaque.
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Progression/complications: Plaques may calcify, ulcerate, rupture, haemorrhage, or become superimposed with thrombus, leading to clinical events such as myocardial infarction, stroke, or peripheral vascular disease.