Key Takeaways & Executive Findings
- •• BMSC-EVs attenuate vascular calcification in type 2 diabetes by inhibiting endothelial ferroptosis. • miR-32 deficiency in BMSC-EVs enhances their protective effect against vascular calcification. • The protective mechanism involves regulation of the MAPK/FoxO signaling pathway. • BMSC-EVs represent a promising cell-free therapeutic strategy for diabetic vascular calcification.
Abstract
Background: The development of vascular calcification (VC) in diabetes is closely related to the endothelial-to-mesenchymal transition (EndMT). We found that microRNA-32-5p (miR-32) was elevated in the plasma of calcification patients. However, it is unclear whether miR-32 mediates the function of bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) in type 2 diabetes (T2D) VC. Methods: BMSC-EVs were characterized by TEM, NTA, Western blotting, and confocal microscopy. Alizarin Red and ALP staining assessed the severity of VC. qRT-PCR and Western blotting evaluated the expression of BMP2, RUNX2, GPX4, SLC7A11, VE-cadherin, and N-cadherin, while immunofluorescence was used for detecting VE-cadherin and N-cadherin. In vivo validation was performed using miR-32–/– and ApoE–/– mice. RNA sequencing (RNA-seq) and bioinformatics analysis was conducted to explore underlying mechanisms. Results: We demonstrated that BMSC-EVs attenuate VC in endothelial cells (ECs) and inhibit EndMT. In vivo, histological analysis showed that treatment with BMSC-EVs significantly reduced the severity of VC associated with T2D. Notably, knockout of miR-32 further enhanced the inhibitory effect of BMSC-EVs on VC. Mechanistically, transcriptomic and functional analyses suggest that the protective effect of BMSC-EVs on VC is associated with regulation of the MAPK/FoxO signaling pathway, potentially mediated by modulation of ferroptosis. Conclusion: These findings demonstrate that BMSC-EVs attenuate T2D-associated VC, partially through miR-32-mediated suppression of EC ferroptosis.
1. Introduction
Vascular calcification (VC), characterized by abnormal mineral deposition in blood vessels, is prevalent in type 2 diabetes (T2D) patients [1, 2]. This process is considered an active and potentially modifiable physiological event. Depending on location, VC can affect the intima, media, valves, or other tissues, with T2D-associated VC primarily involving the intima and media [3, 4]. VC increases vascular stiffness and reduces compliance, leading to elevated pulse pressure, ventricular hypertrophy, altered left ventricular pressure, and changes in coronary artery diameter [5]. Studies have shown that cardiovascular disease is strongly associated with increased mortality from T2D, particularly VC [6, 7]. While some drugs and surgical interventions can mitigate VC progression, effective treatments remain lacking [8]. Addressing VC is crucial for reducing cardiovascular complications and improving T2D prognosis. Therefore, the development of novel and effective therapeutic strategies for VC is urgently needed.
Endothelial-to-mesenchymal transition (EndMT) is a hallmark of VC [9]. During EndMT, endothelial cells (ECs) begin to express markers typically associated with vascular smooth muscle cells (VSMCs) or mesenchymal stem cell-like phenotypes, such as α-SMA, SM22α, VE-cadherin, and N-cadherin [10]. This process can initially help maintain indicators of lesion stability; however, this temporary protective effect diminishes as the condition progresses to more advanced stages [11]. EndMT has also been implicated in various cardiovascular and metabolic diseases, including VC, obesity, hypertension, hyperlipidemia, and T2D. As such, it is increasingly recognized as a potential therapeutic target for vascular diseases.
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Zhengjie Lin, Anqi Li, Jie Zheng, Kun Luo, Fei Liang, Shiyan Liu, Zhengfeng Liang, Wei Liu, Jian Tang, Xiaolin Zhong, Jianghua Liu (2026). Deficiency of extracellular vesicles miR-32 from bone marrow mesenchymal stem cells alleviates vascular calcification in type 2 diabetes by inhibiting endothelial ferroptosis. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-026-04896-8
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Frequently Asked Questions
What is the role of BMSC-EVs in vascular calcification associated with type 2 diabetes?
BMSC-EVs attenuate vascular calcification in type 2 diabetes by inhibiting endothelial ferroptosis, as demonstrated in this study.
How does miR-32 deficiency affect the function of BMSC-EVs?
Knockout of miR-32 further enhances the inhibitory effect of BMSC-EVs on vascular calcification, suggesting that miR-32 in BMSC-EVs partially mediates their protective effect.
What is the underlying mechanism of BMSC-EVs in alleviating vascular calcification?
The protective effect is associated with regulation of the MAPK/FoxO signaling pathway, potentially mediated by modulation of ferroptosis.
What are the potential therapeutic implications of this study?
BMSC-EVs represent a promising cell-free therapeutic strategy for diabetic vascular calcification, and targeting miR-32 could enhance their efficacy.
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