Wnt Signaling Mechanisms in Vascular Smooth Muscle Cells

Wnt signalling comprises a family of secreted glycoproteins that engage cell-surface receptors to regulate cellular behaviour. In vascular smooth muscle cells (VSMCs), this pathway modulates proliferation, migration, phenotypic switching and survival—processes central to vascular development, repair and disease. Canonical Wnt signalling, mediated by β-catenin stabilisation and translocation to the nucleus, influences gene expression via T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional complexes. Non-canonical branches, including planar cell polarity and Wnt/Ca2+ pathways, operate independently of β-catenin to govern cytoskeletal organisation and intracellular calcium dynamics. In the vascular wall, a delicate balance between these branches determines the VSMC phenotype: a contractile state promoting tone and stability, or a synthetic state facilitating extracellular matrix remodelling and lesion formation. Crosstalk with growth factor and inflammatory cues further refines Wnt activity, while co-receptors such as LRP5/6 or Ror2 modulate ligand specificity. Dysregulation of Wnt signalling in VSMCs contributes to pathologies including atherosclerosis, aneurysm formation and restenosis after vascular injury, highlighting its significance as a therapeutic target.

Research from Nature Portfolio

A recent study in an experimental atherosclerosis model has revealed that tetrandrine, a bioactive alkaloid, mitigates plaque progression through modulation of a non-canonical Wnt5a–Ror2 axis. Treatment normalised expression of Wnt5a and its co-receptor Ror2 in the vessel wall and suppressed downstream inflammatory mediators while restoring lipid transport via ABCA1. Concomitant attenuation of NF-κB activation and oxidative stress underscored the intertwined nature of Wnt signalling and inflammatory pathways in VSMC-driven lesion growth. These findings advance the understanding of how targeting specific Wnt branches can confer vascular protection in hyperlipidaemic states.

Wnt Signaling Mechanisms in Vascular Smooth Muscle Cells publication trend

The graph below shows the total number of articles in wnt signaling mechanisms in vascular smooth muscle cells across all publications each year (not limited to Nature Index journals).

Technical terms

Vascular smooth muscle cells (VSMCs): Contractile cells in the arterial wall responsible for vessel tone and structural integrity.

Canonical Wnt pathway: Signalling cascade whereby Wnt ligands bind Frizzled and LRP5/6 co-receptors, leading to β-catenin stabilisation and transcriptional activation via TCF/LEF.

Non-canonical Wnt pathway: β-catenin-independent branches, including planar cell polarity and Wnt/Ca2+ signalling, that regulate cell movement and intracellular calcium.

β-catenin: Intracellular mediator whose nuclear accumulation drives Wnt-dependent gene transcription.

Frizzled receptors: Seven-pass transmembrane proteins that bind Wnt ligands and initiate downstream signalling.

Ror2: Orphan tyrosine kinase co-receptor that confers specificity to Wnt5a signalling in non-canonical pathways.

References

1. Tetrandrine ameliorated atherosclerosis in vitamin D3/high cholesterol diet-challenged rats via modulation of miR-34a and Wnt5a/Ror2/ABCA1/NF-kB trajectory. Scientific Reports (2024).
2. Wnt Signaling in Atherosclerosis: Mechanisms to Therapeutic Implications. Biomedicines (2024).
3. LRP5 deficiency down‐regulates Wnt signalling and promotes aortic lipid infiltration in hypercholesterolaemic mice. Journal of Cellular and Molecular Medicine (2015).
4. Aging differentially modulates the Wnt pro‐survival signalling pathways in vascular smooth muscle cells. Aging Cell (2018).