Mechanisms of Atherosclerotic Plaque Vulnerability and Thrombus Formation

Atherosclerosis progresses through lipid accumulation, chronic inflammation and remodelling of the arterial wall. Endothelial dysfunction allows low‐density lipoproteins to infiltrate the intima, where they undergo oxidation and trigger recruitment of monocytes. Differentiation into macrophages and uptake of lipids form foam cells and drive the expansion of a necrotic core. Concurrently, vascular smooth muscle cells migrate from the media, proliferate and deposit extracellular matrix to form a fibrous cap. Loss of cap integrity through protease‐mediated matrix degradation and cell death yields a thin fibrous cap overlying a lipid‐rich necrotic core. Biomechanical stress, persistent inflammation and enzymatic activity render plaques prone to rupture or erosion, exposing thrombogenic material such as collagen and tissue factor. Platelet adhesion, activation and fibrin deposition then culminate in occlusive thrombus formation, precipitating ischaemic events. Understanding these interconnected cellular, molecular and mechanical processes underpins the development of targeted stabilisation strategies and antithrombotic therapies.

Research from Nature Portfolio

Quantitative proteomic profiling in an animal model that recapitulates human plaque instability has revealed distinct protein signatures of vulnerable lesions, notably elevated markers of innate immune activation and neutrophil degranulation. Among these, the S100A8/A9 calprotectin complex emerged as a central driver of destabilisation, and its pharmacological inhibition was shown to enhance cap thickness and reduce necrotic core size. A complementary study using gene‐targeted mice demonstrated that loss of a macrophage‐expressed ion channel led to reduced endoplasmic reticulum stress and apoptotic M1 macrophage death, thereby decreasing necrosis and preserving fibrous cap integrity. These findings highlight proteomic discovery and macrophage survival pathways as promising avenues for plaque stabilisation.

Mechanisms of Atherosclerotic Plaque Vulnerability and Thrombus Formation publication trend

The graph below shows the total number of articles in mechanisms of atherosclerotic plaque vulnerability and thrombus formation across all publications each year (not limited to Nature Index journals).

Technical terms

Atherosclerotic plaque vulnerability: Propensity of a lesion to rupture or erode due to structural weakness.

Necrotic core: Lipid‐rich, cell-debris region within an atherosclerotic plaque formed by foam-cell death.

Fibrous cap: Collagenous layer overlying the necrotic core that provides mechanical stability.

Vascular smooth muscle cell (VSMC): Intimal cells that synthesise extracellular matrix and influence plaque structure.

Inflammasome: Multiprotein complex that activates caspase-1 and drives secretion of interleukin-1β.

Proteomic profiling: Large-scale identification and quantification of proteins to define disease signatures.

Proteoglycan: Extracellular matrix molecule consisting of a core protein with glycosaminoglycan chains, modulating cell–matrix interactions.

References

1. Quantitative proteomic landscape of unstable atherosclerosis identifies molecular signatures and therapeutic targets for plaque stabilization. Communications Biology (2023).
2. Reduced Necrosis and Content of Apoptotic M1 Macrophages in Advanced Atherosclerotic Plaques of Mice With Macrophage-Specific Loss of Trpc3. Scientific Reports (2017).
3. Nicotine exacerbates atherosclerosis and plaque instability via NLRP3 inflammasome activation in vascular smooth muscle cells. Theranostics (2023).
4. Differential Proteoglycan Expression in Atherosclerosis Alters Platelet Adhesion and Activation. International Journal of Molecular Sciences (2024).
5. Interferon regulatory factor-5-dependent CD11c+ macrophages contribute to the formation of rupture–prone atherosclerotic plaques. European Heart Journal (2022).