Department of Burn Plastic Surgery, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China.
Exp Dermatol. 2022 Sep;31(9):1392-1401. doi: 10.1111/exd.14607. Epub 2022 May 25.
Angiogenesis has been identified to assume a critical role in skin wound healing. Moreover, zinc finger E-box binding homeobox 1 (ZEB1) was capable of promoting skin wound healing. Herein, cell and animal experiments were implemented in this study to figure out whether ZEB1 orchestrated angiogenesis during skin wound healing. Subsequent to gain- and loss-of-function approaches in human dermal microvascular endothelial cells (HDMECs), HDMEC proliferation, migration and angiogenesis were evaluated by CCK8, EdU, wound healing, Transwell and angiogenesis in vitro assays. The relationship among ZEB1, microRNA (miR)-206 and vascular endothelial growth factor A (VEGFA) was assessed by microarray analysis, dual-luciferase, ChIP and RIP assays. Finally, the mechanism of ZEB1 in skin wound healing was confirmed by in vivo experiments. Mechanically, ZEB1 upregulation resulted in miR-206 downregulation by binding to miR-206 promoter, and miR-206 repressed VEGFA expression by directly targeting. ZEB1 overexpression enhanced HDMEC proliferation, migration and angiogenesis, which was neutralized by miR-206 upregulation or VEGFA inhibition. Moreover, ZEB1 significantly promoted skin wound healing in mice, which was negated by overexpression of miR-206. Conclusively, ZEB1 augmented angiogenesis to promote skin wound healing by elevating VEGFA expression via miR-206 repression.
血管生成被认为在皮肤伤口愈合中起关键作用。此外，锌指 E 盒结合同源盒 1（ZEB1）能够促进皮肤伤口愈合。本研究通过细胞和动物实验，研究 ZEB1 是否在皮肤伤口愈合过程中调控血管生成。在人真皮微血管内皮细胞（HDMEC）中采用增益和缺失功能的方法，通过 CCK8、EdU、划痕实验、Transwell 实验和体外血管生成实验评估 HDMEC 的增殖、迁移和血管生成。通过微阵列分析、双荧光素酶报告基因、染色质免疫沉淀（ChIP）和 RNA 免疫沉淀（RIP）实验评估 ZEB1、微小 RNA（miR）-206 和血管内皮生长因子 A（VEGFA）之间的关系。最后，通过体内实验证实了 ZEB1 在皮肤伤口愈合中的作用机制。在机制上，ZEB1 通过结合 miR-206 启动子导致 miR-206 下调，miR-206 通过直接靶向抑制 VEGFA 表达。ZEB1 的过表达增强了 HDMEC 的增殖、迁移和血管生成，这被 miR-206 的过表达或 VEGFA 的抑制所中和。此外，ZEB1 显著促进了小鼠的皮肤伤口愈合，而过表达 miR-206 则否定了这一作用。综上所述，ZEB1 通过抑制 miR-206 来提高 VEGFA 表达，从而增强血管生成，促进皮肤伤口愈合。
