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Discovery of microvascular miRNAs using public gene expression data: miR-145 is expressed in pericytes and is a regulator of Fli1

Erik Larsson12, Peder Fredlund Fuchs3, Johan Heldin3, Irmeli Barkefors3, Cecilia Bondjers1, Guillem Genové4, Christelle Arrondel56, Pär Gerwins3, Christine Kurschat78, Bernhard Schermer78, Thomas Benzing78, Scott J Harvey5, Johan Kreuger3* and Per Lindahl12*

Author Affiliations

1 Wallenberg Laboratory for Cardiovascular Research, Bruna Stråket 16, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden

2 Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden

3 Department of Medical Biochemistry and Microbiology, Uppsala University, Husargatan 3, SE-751 23 Uppsala, Sweden

4 Department of Medical Biochemistry and Biophysics, Division of Matrix Biology, Lab of Vascular Biology, Karolinska Institutet, Scheeles väg, 2 A:3-P:4, SE-171 77 Stockholm, Sweden

5 Inserm U574, Hôpital Necker-Enfants Malades, Equipe Avenir Tour Lavoisier, 6e étage, 149 rue de Sèvres, 75015 Paris, France

6 Université Paris Descartes, Hôpital Necker-Enfants Malades, Equipe Avenir Tour Lavoisier, 6e étage, 149 rue de Sèvres, 75015 Paris, France

7 Department of Medicine and Centre for Molecular Medicine, University of Cologne, Kerpener Str. 62, 50937 Köln, Germany

8 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Kerpener Str. 62, 50937 Köln, Germany

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Genome Medicine 2009, 1:108  doi:10.1186/gm108

Published: 16 November 2009

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.