What question did this study set out to answer?

This research aims to investigate how extracellular vesicles from atherosclerotic plaques affect smooth muscle cell behavior and vascular changes.

March 7, 2026Open Access

Atherosclerotic plaque-derived extracellular vesicles mediate smooth muscle cell phenotypic switching and promote vascular remodeling

Q: What is the clinical evidence from this study?

Study design: Other. Population: Male Ldlr knockout Sprague Dawley rats with induced carotid atherosclerosis by high-fat high-cholesterol diet and partial carotid ligation. Intervention: GW4869 (neutral sphingomyelinase inhibitor) vs. Vehicle control (5% DMSO in saline). Primary outcome: Phenotypic switching of vascular smooth muscle cells (VSMCs) in atherosclerotic plaques measured by expression of VSMC contractile markers and markers LGALS3, PDGFRB, and SCA1.

Key Result

GW4869 inhibited phenotypic switching of VSMCs in atherosclerotic plaques in Ldlr KO rats.

Key Points

This research aims to investigate how extracellular vesicles from atherosclerotic plaques affect smooth muscle cell behavior and vascular changes.
Induced local atherosclerosis in Ldlr knockout rats on a high-cholesterol diet.
Used immunofluorescence, Western blot, and single-cell sequencing to analyze smooth muscle cell changes.
Extracted extracellular vesicles from atherosclerotic tissues using differential centrifugation.
Delivered engineered EVs with specific microRNA in controlled conditions to assess effects on smooth muscle cells.
Phenotypic switching of vascular smooth muscle cells was observed, with decreased contraction markers and increased specific protein markers.
Inhibition of phenotypic switching was achieved with GW4869 treatment.
Extracellular vesicles derived from plaques enhanced the switching of smooth muscle cell phenotype.
miRNA analysis linked miR-23a-3p to the regulation of contractile marker expression through targeted genes.

Structured PICO

Population

Male Ldlr knockout (KO) Sprague Dawley (SD) rats fed a high-fat high-cholesterol diet with partial carotid ligation, primary rat vascular smooth muscle cells (VSMCs), and human carotid artery specimens from endarterectomy.

Intervention

Atherosclerotic plaque-derived EVs (AS-EVs) delivered via chitosan hydrogel, engineered EVs loaded with miR-23a-3p, or GW4869 (0.7 mg/kg twice weekly).

Comparator

Control rats (normal diet), control EVs, or 5% DMSO in saline.

Outcome

VSMC phenotypic switching (expression of contractile vs switching markers) and carotid artery remodeling (neointimal hyperplasia).surrogate

Atherosclerotic plaque-derived extracellular vesicles promote vascular smooth muscle cell phenotypic switching and exacerbate atherosclerosis via the miR-23a-3p/Myl12b pathway.

Limitations

Study performed in a rat model, limiting direct clinical translation to humans.
No quantitative data or statistical results reported for the primary endpoint.
Small sample sizes per group (n=4) may limit robustness.
Lack of reported long-term functional outcomes or clinical events following treatment.

Abstract

Despite the use of lipid-lowering and anti-inflammatory treatments, the progression of atherosclerosis is relentless in most patients. This suggests the presence of in situ pathological factors that continuously exacerbate lesions. We hypothesized that extracellular vesicles (EVs) within the atherosclerotic microenvironment might act as in situ stimulatory factors on vascular smooth muscle cells (VSMCs), thereby exacerbating atherosclerosis. A local atherosclerosis model was induced using Ldlr knockout (Ldlr KO) rats fed a high-cholesterol diet and subjected to partial carotid ligation. Immunofluorescence, Western blot (WB), and single-cell sequencing confirmed the phenotypic switching of VSMCs in atherosclerotic plaques from both rats and humans. The phenotypic switching of VSMCs in atherosclerotic rats was characterized by reduced expression of VSMC contraction markers and increased expression of LGALS3, PDGFRB, and SCA1. GW4869 inhibited the phenotypic switching of VSMCs in atherosclerotic plaques in a rat model. EVs were extracted from atherosclerotic carotid tissues using differential centrifugation. Chitosan thermosensitive hydrogels were used for in situ delivery of EVs into the arterial wall of the carotid artery. Immunofluorescence staining revealed that atherosclerotic plaque-derived EVs (AS-EVs) promoted VSMC phenotypic switching and downregulated the expression of VSMC contractile markers in vitro. miRNA analysis of EVs derived from atherosclerotic plaques of rats identified miR-23a-3p and its target gene Myl12b. To investigate the underlying mechanisms, engineered EVs loaded with miR-23a-3p were used to mimic AS-EVs. AS-EVs potentially regulate MRTFA nuclear translocation via miR-23a-3p/Myl12b, inhibit contractile marker expression, promote VSMC phenotypic switching, and further promote carotid artery remodelling. We conclude that AS-EVs promote VSMC phenotypic switching and exacerbate atherosclerosis.

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Cite This Study

Wang et al. (Thu,) conducted a other in Male Ldlr knockout Sprague Dawley rats with induced carotid atherosclerosis by high-fat high-cholesterol diet and partial carotid ligation. GW4869 (neutral sphingomyelinase inhibitor) vs. Vehicle control (5% DMSO in saline) was evaluated on Phenotypic switching of vascular smooth muscle cells (VSMCs) in atherosclerotic plaques measured by expression of VSMC contractile markers and markers LGALS3, PDGFRB, and SCA1. GW4869 inhibited phenotypic switching of VSMCs in atherosclerotic plaques in Ldlr KO rats.

synapsesocial.com/papers/69abc1845af8044f7a4ea30b https://doi.org/https://doi.org/10.1007/s00018-026-06094-4

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