Discovery of microvascular miRNAs using public gene expression data: miR-145 is expressed in pericytes and is a regulator of Fli1.
Discovery of microvascular miRNAs using public gene expression data: miR-145 is expressed in pericytes and is a regulator of Fli1.
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DOI：
10.1186/gm108
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发表时间：
2009-11-16
期刊：
影响因子：
12.3
通讯作者：
Lindahl P
中科院分区：
文献类型：
--
作者：
Larsson E;Fredlund Fuchs P;Heldin J;Barkefors I;Bondjers C;Genové G;Arrondel C;Gerwins P;Kurschat C;Schermer B;Benzing T;Harvey SJ;Kreuger J;Lindahl P
microRNA（miRNA）通路在血管发育和血管生成中的功能已经被牢固地确立。在血管系统中具有选择性表达的miRNA作为基于miRNA的治疗中的可能靶点是有吸引力的。然而，关于miRNAs在体内微血管中的表达知之甚少。在这里，我们通过筛选公开的miRNA表达数据集来鉴定候选微血管选择性miRNA。利用实时定量逆转录PCR对小鼠微血管片段进行了微血管选择性表达的生物信息学预测。组织切片原位杂交显示周细胞表达。用3' UTR荧光素酶测定鉴定靶位点，并在微流体趋化室中测试迁移。miR-145、miR-126、miR-24和miR-23 a在从一系列组织分离的微血管片段中选择性表达。Pdgfb保留基序突变小鼠的原位杂交和分析表明miR-145在周细胞中的主要表达。我们将Ets转录因子Friend白血病病毒整合1（Fli 1）确定为miR-145靶点，并表明miR-145水平升高会降低微血管细胞对体外生长因子梯度的迁移反应。miR-126、miR-24和miR-23 a在体内微血管内皮细胞中选择性表达，而miR-145在周细胞中表达。miR-145靶向造血转录因子Fli 1并阻断响应生长因子梯度的迁移。我们的研究结果对血管疾病有意义，并为未来针对微血管中选择性表达的miRNA的药物设计提供必要的信息。
A function for the microRNA (miRNA) pathway in vascular development and angiogenesis has been firmly established. miRNAs with selective expression in the vasculature are attractive as possible targets in miRNA-based therapies. However, little is known about the expression of miRNAs in microvessels in vivo. Here, we identified candidate microvascular-selective miRNAs by screening public miRNA expression datasets. Bioinformatics predictions of microvascular-selective expression were validated with real-time quantitative reverse transcription PCR on purified microvascular fragments from mouse. Pericyte expression was shown with in situ hybridization on tissue sections. Target sites were identified with 3' UTR luciferase assays, and migration was tested in a microfluid chemotaxis chamber. miR-145, miR-126, miR-24, and miR-23a were selectively expressed in microvascular fragments isolated from a range of tissues. In situ hybridization and analysis of Pdgfb retention motif mutant mice demonstrated predominant expression of miR-145 in pericytes. We identified the Ets transcription factor Friend leukemia virus integration 1 (Fli1) as a miR-145 target, and showed that elevated levels of miR-145 reduced migration of microvascular cells in response to growth factor gradients in vitro. miR-126, miR-24 and miR-23a are selectively expressed in microvascular endothelial cells in vivo, whereas miR-145 is expressed in pericytes. miR-145 targets the hematopoietic transcription factor Fli1 and blocks migration in response to growth factor gradients. Our findings have implications for vascular disease and provide necessary information for future drug design against miRNAs with selective expression in the microvasculature.
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影响因子：
64.8
作者：
Cordes KR;Sheehy NT;White MP;Berry EC;Morton SU;Muth AN;Lee TH;Miano JM;Ivey KN;Srivastava D
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Srivastava D
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Mirbase：MicroRNA基因组学的工具。
影响因子：
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作者：
Griffiths-Jones, Sam;Saini, Harpreet Kaur;van Dongen, Stijn;Enright, Anton J.
通讯作者：
Enright, Anton J.