This study identifies a PlGF/anti-inflammatory macrophage/TGF-β1/contractile VSMCs signaling axis that reinforces fibrous cap integrity and promotes plaque stability in advanced atherosclerosis.
PlGF expression was elevated in stable human carotid plaques and co-localized with α-SMA in the fibrous cap and shoulder regions.
In ApoE-/- mice on a high-fat diet, PlGF administration increased PlGF, α-SMA and TGF-β1 in the fibrous cap and shoulder regions of plaques.
PlGF treatment decreased aortic root plaque area in mice.
PlGF treatment enhanced co-localization of Flt-1 with CD209 and of TGF-β1 with CD209 in plaques, with TGF-β1/CD209 co-localization exceeding TGF-β1/α-SMA.
In vitro, PlGF polarized macrophages toward an anti-inflammatory phenotype and increased their TGF-β1 secretion.
Macrophage-derived TGF-β1 upregulated α-SMA in human carotid VSMCs, supporting a contractile phenotype.
The authors propose a PlGF/anti-inflammatory macrophage/TGF-β1/contractile VSMC signaling axis that reinforces fibrous cap integrity and promotes plaque stability.
Atherosclerotic plaques in arteries can be stable or prone to rupture, which causes heart attacks and strokes. Smooth muscle cells in the artery wall help determine this: when they take on a 'contractile' form, they strengthen the plaque's protective fibrous cap. This study asked how a protein called placental growth factor (PlGF), which has been linked to stable plaques in patients, might promote that effect. The researchers found more PlGF in stable human carotid plaques, especially in the fibrous cap where it overlapped with a smooth muscle marker. In atherosclerosis-prone mice, a 7-day PlGF treatment increased smooth muscle and TGF-β1 markers in the cap and shoulder regions and reduced plaque area in the aortic root. Cell experiments suggested PlGF pushes immune cells called macrophages toward an anti-inflammatory state. These macrophages release more TGF-β1, which in turn encourages smooth muscle cells to adopt the contractile, stabilizing form. This research suggests PlGF could help strengthen plaques through a chain of effects involving macrophages and TGF-β1. The findings come from human tissue samples, mice and cell cultures, so they do not show that PlGF-based treatment would work or be safe in people. They do point to a pathway that might be explored for promoting plaque stability.
Li J, Yu Q, Bao J, Sun Z, Hou L, Zhang J, et al.. (2026). PlGF modulates vascular smooth muscle cells phenotype to enhance atherosclerotic plaque stability.. Atherosclerosis. https://doi.org/10.1016/j.atherosclerosis.2026.121929