ArticleArteriosclerosis, thrombosis, and vascular biology2025
ECM Modifications Driven by Age and Metabolic Stress Directly Promote Vascular Smooth Muscle Cell Osteogenic Processes.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Vascular calcification: pathogenic mechanisms, signaling crosstalk and translational therapeutics.Signal transduction and targeted therapy · 2026Review
- Neuro-Mechanical Regulation of Vascular Smooth Muscle Cell Behaviour Under Ageing-Associated Substrate Stiffness.Current issues in molecular biology · 2026Article
- Serum Advanced Glycation End Products as Drivers of Poor Tendon Outcomes in Diabetes? An Emerging Hypothesis and Narrative Review.Endocrinology, diabetes & metabolism · 2026Review
- Distinct effects of aging and klotho deletion on the choroid plexus.GeroScience · 2026Article
- Study on the Effect and Mechanism of the Outer Membrane Vesicles ofMicroorganisms · 2026Article
- Defining the Tumor-Bone axis: the role of extracellular vesicles in a crucial exchange route for breast cancer development and progression.Clinical & experimental metastasis · 2025Review
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7 authors.
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Abstract
backgroundThe ECM (extracellular matrix) provides the microenvironmental niche sensed by resident vascular smooth muscle cells (VSMCs). Aging and disease are associated with dramatic changes in ECM composition and properties; however, their impact on VSMC phenotype remains poorly studied.
methodsHere, we describe a novel in vitro model system that utilizes endogenous ECM to study how modifications associated with age and metabolic disease impact VSMC phenotype. ECM was synthesized using primary human VSMCs and modified during culture or after decellularization. Integrity, stiffness, and composition of the ECM was measured using superresolution microscopy, atomic force microscopy, and proteomics, respectively. VSMCs reseeded onto the modified ECM were analyzed for viability and osteogenic differentiation.
resultsECMs produced in response to mineral stress showed extracellular vesicle-mediated hydroxyapatite deposition and sequential changes in collagen composition and ECM properties. VSMCs seeded onto the calcified ECM exhibited increased extracellular vesicle release and Runx2 (Runt-related transcription factor 2)-mediated osteogenic gene expression due to the uptake of hydroxyapatite, which led to increased reactive oxygen species and the induction of DNA damage signaling. VSMCs seeded onto the nonmineralized, senescent ECM also exhibited increased Runx2-mediated osteogenic gene expression and accelerated calcification. In contrast, glycated ECM specifically induced increased ALP (alkaline phosphatase) activity, and this was dependent on RAGE (receptor for advanced glycation end products) signaling with both ALP and RAGE receptor inhibition attenuating calcification.
conclusionsECM modifications associated with aging and metabolic disease can directly induce osteogenic differentiation of VSMCs via distinct mechanisms and without the need for additional stimuli. This highlights the importance of the ECM microenvironment as a key driver of phenotypic modulation acting to accelerate age-associated vascular pathologies and provides a novel model system to study the mechanisms of calcification.
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