Transforming Growth Factor Signaling in Atherosclerotic Disease

Transforming growth factor-β (TGF-β) signalling plays a pivotal role in the onset, progression and stability of atherosclerotic plaques. TGF-β ligands interact with type I and II serine/threonine kinase receptors on endothelial cells, vascular smooth muscle cells (VSMCs) and inflammatory cells to trigger both Smad-dependent and Smad-independent cascades. Activation of Smad2/3 promotes extracellular matrix (ECM) synthesis, collagen deposition and VSMC differentiation, thereby reinforcing the fibrous cap that overlies lipid-rich cores. Non-Smad pathways—including p38 MAP kinase—contribute to proteoglycan synthesis and cell proliferation. Although TGF-β can exert anti-inflammatory and stabilising effects in early lesions, excessive or dysregulated signalling may foster maladaptive remodelling, matrix degradation and plaque vulnerability. Metabolic comorbidities such as diabetes mellitus further modulate TGF-β bioavailability and receptor activity, exacerbating fibrous cap thinning and increasing the risk of rupture. Understanding the isoform-specific actions of TGF-β1, ‑β2 and ‑β3, as well as their interplay with extracellular proteases and cellular receptors, offers avenues for targeted interventions to preserve plaque integrity and prevent acute cardiovascular events.

Research from Nature Portfolio

Recent studies have used integrative multi-omics and functional assays to elucidate how impaired activation of TGF-β2 undermines fibrous cap formation in diabetic atherosclerosis. Reduced levels of free TGF-β2 in plaques from type 2 diabetes patients were linked to diminished collagen content and weaker VSMC-derived matrix deposition. Mechanistic investigations revealed that MMP2-mediated release of latent TGF-β2 is attenuated by hyperglycaemia, leading to compromised Smad2/3 signalling in contractile VSMCs. Restoration of TGF-β2 activation improved cap stability in experimental models, highlighting a potential therapeutic strategy for reinforcing plaque resilience in high-risk metabolic contexts.

Transforming Growth Factor Signaling in Atherosclerotic Disease publication trend

The graph below shows the total number of articles in transforming growth factor signaling in atherosclerotic disease across all publications each year (not limited to Nature Index journals).

Technical terms

Transforming growth factor-β (TGF-β): A family of cytokines (isoforms 1–3) that regulate cell growth, ECM production and inflammation via receptor-mediated Smad and non-Smad pathways.

Vascular smooth muscle cell (VSMC): Contractile cells in the arterial wall that can switch phenotype to produce ECM components and contribute to plaque structure.

Smad proteins: Intracellular mediators phosphorylated by TGF-β receptors, translocating to the nucleus to control gene transcription.

Fibrous cap: A collagen-rich layer formed by VSMCs and ECM overlying the lipid core of an atherosclerotic plaque, whose integrity prevents rupture.

Matrix metalloproteinase (MMP): Proteolytic enzymes that degrade ECM components and regulate activation of latent TGF-β.

References

1. Smad and p38 MAP Kinase-mediated Signaling of Proteoglycan Synthesis in Vascular Smooth Muscle*. Journal of Biological Chemistry (2008).
2. Dysregulation of MMP2-dependent TGF-ß2 activation impairs fibrous cap formation in type 2 diabetes-associated atherosclerosis. Nature Communications (2024).
3. Transforming growth factor-β2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events. Cardiovascular Research (2023).
4. TGF-β Isoforms and GDF-15 in the Development and Progression of Atherosclerosis. International Journal of Molecular Sciences (2024).
5. Targeting serotonin receptor 2B inhibits TGFβ induced differentiation of human vascular smooth muscle cells. European Journal of Pharmacology (2023).