Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China.
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
J Vasc Surg Venous Lymphat Disord. 2022 Mar;10(2):469-481.e2. doi: 10.1016/j.jvsv.2021.08.020. Epub 2021 Sep 22.
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.
The expression of miR-21, collagen I, III, and IV, transforming growth factor-β (TGF-β), 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.
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-β/Smad3 pathway in VMs. Moreover, our data demonstrated that miR-21 positively regulated the expression of collagens in HUVECs and showed a positive association with the TGF-β/Smad3 pathway in the VM tissues. In addition, miR-21 was found to mediate TGF-β-induced upregulation of collagens in HUVECs. Our data have indicated that miR-21 and the TGF-β/Smad3 pathway could form a positive feedback loop to synergistically regulate endothelial collagen synthesis. In addition, TGF-β/Smad3/miR-21 feedback loop signaling was upregulated in bleomycin-treated HUVECs and VM specimens, which was accompanied by increased collagen deposition.
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-β/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.
静脉畸形（VMs）是最常见的血管畸形，其特征为扩张和扭曲的静脉以及失调的血管细胞外基质。本研究旨在探讨多功能 microRNA-21（miR-21），一种与细胞外基质调节密切相关的 microRNA，在 VMs 发病机制中的潜在作用。
通过原位杂交、免疫组织化学、Masson 三色染色和实时聚合酶链反应，评估 miR-21、胶原 I、III 和 IV、转化生长因子-β（TGF-β）和 Smad3（母亲抗 Decapentaplegic 同源物 3）在 VMs 和正常皮肤组织中的表达。使用人脐静脉内皮细胞（HUVECs）来探索潜在机制。
与正常皮肤相比，VM 标本中 miR-21 的表达明显降低，同时 VMs 中胶原 I、III 和 IV 以及 TGF-β/Smad3 通路下调。此外，我们的数据表明 miR-21 可正向调节 HUVECs 中胶原的表达，并与 VM 组织中的 TGF-β/Smad3 通路呈正相关。此外，发现 miR-21 可介导 TGF-β 诱导的 HUVECs 中胶原的上调。我们的数据表明，miR-21 和 TGF-β/Smad3 通路可以形成正反馈环，协同调节内皮胶原合成。此外，在博来霉素处理的 HUVECs 和 VM 标本中，TGF-β/Smad3/miR-21 反馈环信号上调，伴随着胶原沉积增加。
据我们所知，本研究首次揭示了 VMs 中 miR-21 的下调，这可能通过 TGF-β/Smad3/miR-21 信号反馈环导致胶原表达减少。这些发现为 VMs 的发病机制提供了新的信息，并可能为 VMs 的治疗提供新的方法。
