Wang Shusheng, Aurora Arin B, Johnson Brett A, Qi Xiaoxia, McAnally John, Hill Joseph A, Richardson James A, Bassel-Duby Rhonda, Olson Eric N
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Dev Cell. 2008 Aug;15(2):261-71. doi: 10.1016/j.devcel.2008.07.002.
Endothelial cells play essential roles in maintenance of vascular integrity, angiogenesis, and wound repair. We show that an endothelial cell-restricted microRNA (miR-126) mediates developmental angiogenesis in vivo. Targeted deletion of miR-126 in mice causes leaky vessels, hemorrhaging, and partial embryonic lethality, due to a loss of vascular integrity and defects in endothelial cell proliferation, migration, and angiogenesis. The subset of mutant animals that survives displays defective cardiac neovascularization following myocardial infarction. The vascular abnormalities of miR-126 mutant mice resemble the consequences of diminished signaling by angiogenic growth factors, such as VEGF and FGF. Accordingly, miR-126 enhances the proangiogenic actions of VEGF and FGF and promotes blood vessel formation by repressing the expression of Spred-1, an intracellular inhibitor of angiogenic signaling. These findings have important therapeutic implications for a variety of disorders involving abnormal angiogenesis and vascular leakage.
内皮细胞在维持血管完整性、血管生成和伤口修复中发挥着重要作用。我们发现一种内皮细胞特异性微小RNA（miR-126）在体内介导发育性血管生成。在小鼠中靶向缺失miR-126会导致血管渗漏、出血和部分胚胎致死，这是由于血管完整性丧失以及内皮细胞增殖、迁移和血管生成缺陷所致。存活下来的突变动物亚群在心肌梗死后表现出心脏新生血管形成缺陷。miR-126突变小鼠的血管异常类似于血管生成生长因子（如VEGF和FGF）信号传导减弱的后果。因此，miR-126增强了VEGF和FGF的促血管生成作用，并通过抑制血管生成信号的细胞内抑制剂Spred-1的表达来促进血管形成。这些发现对于涉及异常血管生成和血管渗漏的多种疾病具有重要的治疗意义。
