期刊
JOURNAL OF VASCULAR SURGERY-VENOUS AND LYMPHATIC DISORDERS
卷 10, 期 2, 页码 469-+出版社
ELSEVIER
DOI: 10.1016/j.jvsv.2021.08.020
关键词
Collagen; Feedback loop; miR-21; TGF-beta; Venous malformations
资金
- National Natural Science Foundation of China [81803113, 81600385]
- Natural Science Foundation of Hubei Province [2018CFB201, 2019CFB716]
- Key Laboratory Fund of Wuhan Union Hospital [02.03.2018-81]
- Free Innovation Fund of Wuhan Union Hospital [02.03.2017-42]
- Open Research Fund Program of Hubei-MOST KLOS KLOBME [202001]
- Fundamental Research Funds for the Central Universities [2020kfyXGYJ082]
- China Scholarship Council [201906165065]
This study revealed for the first time the downregulation of miR-21 in venous malformations (VMs), which may contribute to decreased collagen expression through the TGF-beta/Smad3/miR-21 signaling feedback loop. These findings provide new insights into the pathogenesis of VMs and may facilitate the development of new therapeutic approaches.
Objective: Venous malformations (VMs) are the most frequent vascular malformations and are characterized by dilated and tortuous veins with a dysregulated vascular extracellular matrix. The purpose of the present study was to investigate the potential involvement of microRNA-21 (miR-21), a multifunctional microRNA tightly associated with extracellular matrix regulation, in the pathogenesis of VMs. Methods: The expression of miR-21, collagen I, III, and IV, transforming growth factor-beta (TGF-beta), and Smad3 (mothers against decapentaplegic homolog 3) was evaluated in VMs and normal skin tissue using in situ hybridization, immunohistochemistry, Masson trichrome staining, and real-time polymerase chain reaction. Human umbilical vein endothelial cells (HUVECs) were used to explore the underlying mechanisms. Results: miR-21 expression was markedly decreased in the VM specimens compared with normal skin, in parallel with downregulation of collagen I, III, and IV and the TGF-beta/Smad3 pathway in VMs. Moreover, our data demonstrated that miR21 positively regulated the expression of collagens in HUVECs and showed a positive association with the TGF-beta/Smad3 pathway in the VM tissues. In addition, miR-21 was found to mediate TGF-beta-induced upregulation of collagens in HUVECs. Our data have indicated that miR-21 and the TGF-beta/Smad3 pathway could form a positive feedback loop to synergistically regulate endothelial collagen synthesis. In addition, TGF-beta/Smad3/miR-21 feedback loop signaling was upregulated in bleomycin-treated HUVECs and VM specimens, which was accompanied by increased collagen deposition. Conclusions: To the best of our knowledge, the present study has, for the first time, revealed downregulation of miR-21 in VMs, which might contribute to decreased collagen expression via the TGF-beta/Smad3/miR-21 signaling feedback loop. These findings provide new information on the pathogenesis of VMs and might facilitate the development of new therapies for VMs.
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