Atherosclerosis Pathogenesis—Mechanisms at Work

Atherosclerosis is a progressive disease characterized by plaque buildup in arterial walls, reducing blood flow and increasing cardiovascular risk. It develops over decades and involves complex biological interactions beyond simple cholesterol accumulation.

Understanding its mechanisms reveals how lifestyle, genetics, and systemic factors influence its progression.

Endothelial Dysfunction

The endothelium, a single layer of cells lining blood vessels, regulates blood flow, permeability, and coagulation balance. Under normal conditions, endothelial cells produce nitric oxide (NO), a vasodilator that maintains vessel flexibility and inhibits platelet aggregation. However, chronic stressors like hypertension, hyperglycemia, and oxidized low-density lipoprotein (LDL) impair endothelial function, initiating atherosclerosis. Reduced NO bioavailability, often due to oxidative stress and asymmetric dimethylarginine (ADMA) accumulation, leads to vasoconstriction and increased vascular resistance, worsening endothelial injury.

Dysfunctional endothelial cells express adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), promoting monocyte attachment. E-selectin further facilitates leukocyte adhesion. Once monocytes penetrate the subendothelial space, they encounter a pro-oxidative environment rich in reactive oxygen species (ROS) and modified lipoproteins. Dysfunctional endothelial mitochondria contribute to oxidative stress, degrading NO and perpetuating vascular damage.

Endothelial dysfunction also disrupts the balance between pro- and anticoagulant factors. Normally, endothelial cells express thrombomodulin and tissue factor pathway inhibitor (TFPI) to prevent excessive coagulation. In dysfunction, tissue factor and plasminogen activator inhibitor-1 (PAI-1) increase, fostering a prothrombotic state that promotes microthrombi formation and arterial narrowing. Additionally, impaired endothelial permeability allows lipoproteins and inflammatory mediators to infiltrate the arterial wall, exacerbating disease progression.

Lipoprotein Retention and Foam Cell Formation

Endothelial dysfunction compromises arterial integrity, permitting LDL infiltration into the subendothelial space. However, LDL alone does not drive atherosclerosis; its retention and modification within the intima initiate pathological changes. Proteoglycans like biglycan and decorin bind LDL, trapping it in the extracellular matrix and increasing its susceptibility to oxidation and enzymatic modification. Oxidized LDL (oxLDL) is no longer recognized by traditional LDL receptors and instead interacts with scavenger receptors on arterial cells.

Smooth muscle and endothelial cells release secretory phospholipase A2 (sPLA2) and myeloperoxidase (MPO), further degrading LDL into highly oxidized forms. These modified particles generate bioactive lipids that disrupt cellular homeostasis and promote inflammation. Oxidized phospholipids stimulate monocyte chemoattractant protein-1 (MCP-1) expression, enhancing immune cell recruitment. Lipoproteins aggregate into cholesterol-rich deposits, forming the foundation of plaque.

Macrophages attempt to clear oxidized lipoproteins by engulfing them through scavenger receptors such as CD36 and scavenger receptor-A (SR-A). Unlike traditional LDL uptake, this process lacks feedback inhibition, allowing macrophages to accumulate excessive lipids. Over time, these macrophages transform into foam cells—lipid-laden cells that drive plaque expansion and necrotic core formation.

Immuno-Inflammatory Cascade

Lipoprotein accumulation triggers a sustained inflammatory response, converting a lipid deposit into an active lesion. The immune system perceives oxidized lipoproteins as danger-associated molecular patterns (DAMPs), activating pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) on macrophages and dendritic cells. This activation leads to pro-inflammatory cytokine release, including interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), which recruit additional immune cells. The NLRP3 inflammasome senses oxidative stress and cholesterol crystals, activating caspase-1 and promoting IL-1β maturation, further amplifying inflammation.

T cells, particularly pro-inflammatory CD4+ subsets, infiltrate the lesion and secrete interferon-gamma (IFN-γ), which exacerbates macrophage activation. Regulatory T cells (Tregs), typically involved in immune suppression, are often impaired in advanced plaques, promoting chronic inflammation. B2 cells contribute by producing pro-atherogenic IgG antibodies, while B1 cells generate natural IgM antibodies that may neutralize modified lipoproteins. The balance between innate and adaptive immunity influences inflammation and plaque stability.

Neutrophils also contribute by releasing neutrophil extracellular traps (NETs), which sustain macrophage activation and endothelial dysfunction. Mast cells degranulate in response to inflammatory signals, releasing proteases that degrade extracellular matrix components and increase vascular permeability, reinforcing immune cell infiltration.

Smooth Muscle Migration and Extracellular Matrix Changes

As lesions progress, structural remodeling of the arterial wall occurs, driven by vascular smooth muscle cells (VSMCs) migrating from the medial layer into the intima. Normally, VSMCs regulate vascular tone and extracellular matrix (ECM) homeostasis. However, in response to platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β), they shift from a contractile to a synthetic phenotype, proliferating and secreting ECM components. This forms a fibrous cap that stabilizes plaques but can also contribute to maladaptive changes.

The ECM composition, including collagen, elastin, and proteoglycans, determines plaque stability. Collagen types I and III, produced by VSMCs, reinforce the fibrous cap. However, an imbalance in ECM turnover—driven by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs)—can weaken the plaque. MMP-9 degrades type IV collagen and elastin, increasing cap thinning risk. Excessive proteoglycan deposition further alters lesion structure, promoting lipoprotein retention and calcification.

Plaque Development and Instability

Mature plaques vary in stability depending on their structural composition. Stable plaques have thick fibrous caps composed of type I and III collagen, reinforced by VSMCs. However, an imbalance in ECM synthesis and degradation can lead to cap thinning. MMPs, particularly MMP-2 and MMP-9, degrade collagen and elastin, weakening the plaque. Simultaneously, VSMC apoptosis reduces ECM replenishment, further compromising structural integrity. Necrotic debris accumulation increases mechanical stress, making plaques prone to rupture.

When a plaque ruptures, its thrombogenic contents, including tissue factor and apoptotic debris, interact with circulating platelets and coagulation factors. This triggers an acute thrombotic response, forming an occlusive clot. Platelets adhere to the exposed subendothelial matrix via glycoprotein receptors like GPIb-IX-V, which bind von Willebrand factor. Platelet activation releases thromboxane A2 and adenosine diphosphate (ADP), amplifying aggregation and fibrin deposition. The extent of thrombus formation dictates clinical outcomes, from transient ischemia to complete arterial occlusion. In coronary arteries, this process underlies acute coronary syndromes, including myocardial infarction. In cerebral arteries, plaque rupture can lead to ischemic stroke.

The interplay between plaque composition, mechanical stress, and thrombotic potential determines whether an atherosclerotic lesion remains subclinical or causes a life-threatening vascular event.