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首页> 外文期刊>Circulation research: a journal of the American Heart Association >MicroRNA-223 antagonizes angiogenesis by targeting β1 integrin and preventing growth factor signaling in endothelial cells
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MicroRNA-223 antagonizes angiogenesis by targeting β1 integrin and preventing growth factor signaling in endothelial cells

机译：MicroRNA-223通过靶向β1整合素并阻止内皮细胞中的生长因子信号传导来拮抗血管生成

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RATIONALE: Endothelial cells in situ are largely quiescent, and their isolation and culture are associated with the switch to a proliferative phenotype. OBJECTIVE: To identify antiangiogenic microRNAs expressed by native endothelial cells that are altered after isolation and culture, as well as the protein targets that regulate responses to growth factors. METHODS AND RESULTS: Profiling studies revealed that miR-223 was highly expressed in freshly isolated human, murine, and porcine endothelial cells, but those levels decreased in culture. In primary cultures of endothelial cells, vascular endothelial cell growth factor and basic fibroblast growth factor further decreased miR-223 expression. The overexpression of precursor-miR-223 did not affect basal endothelial cell proliferation but abrogated vascular endothelial cell growth factor-induced and basic fibroblast growth factor-induced proliferation, as well as migration and sprouting. Inhibition of miR-223 in vivo using specific antagomirs potentiated postnatal retinal angiogenesis in wild-type mice, whereas recovery of perfusion after femoral artery ligation and endothelial sprouting from aortic rings from adult miR-223 animals were enhanced. MiR-223 overexpression had no effect on the growth factor-induced activation of ERK1/2 but inhibited the vascular endothelial cell growth factor-induced and basic fibroblast growth factor-induced phosphorylation of their receptors and activation of Akt. β1 integrin was identified as a target of miR-223 and its downregulation reproduced the defects in growth factor receptor phosphorylation and Akt signaling seen after miR-223 overexpression. Reintroduction of β1 integrin into miR-223-ovexpressing cells was sufficient to rescue growth factor signaling and angiogenesis. CONCLUSIONS: These results indicate that miR-223 is an antiangiogenic microRNA that prevents endothelial cell proliferation at least partly by targeting β1 integrin.
机译：理由：内皮细胞原位处于静止状态，其分离和培养与向增殖表型的转变有关。目的：鉴定天然内皮细胞表达的在分离和培养后发生改变的抗血管生成微RNA，以及调节对生长因子反应的蛋白质靶标。方法和结果：分析研究表明，miR-223在新鲜分离的人，鼠和猪内皮细胞中高表达，但在培养物中这些水平下降。在内皮细胞的原代培养中，血管内皮细胞生长因子和碱性成纤维细胞生长因子进一步降低了miR-223的表达。前体-miR-223的过表达并不影响基底内皮细胞的增殖，但可以消除血管内皮细胞生长因子诱导的和碱性成纤维细胞生长因子诱导的增殖以及迁移和发芽。在野生型小鼠体内使用特定的拟南芥抑制miR-223可增强出生后的视网膜血管生成，而从成年miR-223动物的股动脉结扎和主动脉环上的内皮萌发后的灌注恢复则得到增强。 MiR-223过表达对生长因子诱导的ERK1 / 2激活没有影响，但抑制了血管内皮细胞生长因子诱导的和碱性成纤维细胞生长因子诱导的受体的磷酸化和Akt的激活。 β1整联蛋白被确定为miR-223的靶标，其下调重现了miR-223过表达后生长因子受体磷酸化和Akt信号转导的缺陷。将β1整联蛋白重新引入miR-223表达的细胞中足以拯救生长因子信号传导和血管生成。结论：这些结果表明miR-223是一种抗血管生成的microRNA，可通过靶向β1整联蛋白至少部分地阻止内皮细胞增殖。

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