Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Medical Biology, Hacettepe University, Ankara, Turkey.
FASEB J. 2019 Apr;33(4):5599-5614. doi: 10.1096/fj.201802063RR. Epub 2019 Jan 22.
Angiogenesis is a critical process in repair of tissue injury that is regulated by a delicate balance between pro- and antiangiogenic factors. In disease states associated with impaired angiogenesis, we identified that miR-135a-3p is rapidly induced and serves as an antiangiogenic microRNA (miRNA) by targeting endothelial cell (EC) p38 signaling in vitro and in vivo. MiR-135a-3p overexpression significantly inhibited EC proliferation, migration, and network tube formation in matrigel, whereas miR-135-3p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3'-UTR reporter and miRNA ribonucleoprotein complex -immunoprecipitation assays, and small interfering RNA dependency studies revealed that miR-135a-3p inhibits the p38 signaling pathway in ECs by targeting huntingtin-interacting protein 1 (HIP1). Local delivery of miR-135a-3p inhibitors to wounds of diabetic db/db mice markedly increased angiogenesis, granulation tissue thickness, and wound closure rates, whereas local delivery of miR-135a-3p mimics impaired these effects. Finally, through gain- and loss-of-function studies in human skin organoids as a model of tissue injury, we demonstrated that miR-135a-3p potently modulated p38 signaling and angiogenesis in response to VEGF stimulation by targeting HIP1. These findings establish miR-135a-3p as a pivotal regulator of pathophysiological angiogenesis and tissue repair by targeting a VEGF-HIP1-p38K signaling axis, providing new targets for angiogenic therapy to promote tissue repair.-Icli, B., Wu, W., Ozdemir, D., Li, H., Haemmig, S., Liu, X., Giatsidis, G., Cheng, H. S., Avci, S. N., Kurt, M., Lee, N., Guimaraes, R. B., Manica, A., Marchini, J. F., Rynning, S. E., Risnes, I., Hollan, I., Croce, K., Orgill, D. P., Feinberg, M. W. MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.
血管生成是组织损伤修复的关键过程，由促血管生成和抗血管生成因子之间的微妙平衡来调节。在与血管生成受损相关的疾病状态下，我们发现 miR-135a-3p 被迅速诱导，并通过靶向体外和体内内皮细胞 (EC) p38 信号而作为一种抗血管生成 microRNA (miRNA)。miR-135a-3p 的过表达显著抑制了 EC 在基质胶中的增殖、迁移和网络管形成，而 miR-135a-3p 的中和作用则产生相反的效果。通过转录组谱分析、生物信息学、3'-UTR 报告和 miRNA 核糖核蛋白复合物免疫沉淀测定以及小干扰 RNA 依赖性研究的机制研究表明，miR-135a-3p 通过靶向亨廷顿相互作用蛋白 1 (HIP1) 抑制 EC 中的 p38 信号通路。将 miR-135a-3p 抑制剂局部递送至糖尿病 db/db 小鼠的伤口，显著增加了血管生成、肉芽组织厚度和伤口闭合率，而局部递送 miR-135a-3p 模拟物则损害了这些效果。最后，通过在皮肤类器官中进行增益和失能研究，作为组织损伤的模型，我们证明 miR-135a-3p 通过靶向 HIP1 来调节 VEGFA 刺激下的 p38 信号和血管生成，从而成为 VEGF-HIP1-p38K 信号轴的关键调节因子，为促进组织修复的血管生成治疗提供了新的靶点。-Icli，B.，Wu，W.，Ozdemir，D.，Li，H.，Haemmig，S.，Liu，X.，Giatsidis，G.，Cheng，H. S.，Avci，S. N.，Kurt，M.，Lee，N.，Guimaraes，R. B.，Manica，A.，Marchini，J. F.，Rynning，S. E.，Risnes，I.，Hollan，I.，Croce，K.，Orgill，D. P.，Feinberg，M. W.。miR-135a-3p 通过靶向内皮细胞中的 p38 信号调节血管生成和组织修复。
