Abstract
BackgroundA 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.MethodsBioinformatics 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.ResultsmiR-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.ConclusionsmiR-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.
Highlights
A function for the microRNA 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
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 Friend leukemia virus integration 1 (Fli1) and blocks migration in response to growth factor gradients
Data were gathered from three different sources: a set of small RNA sequence libraries of varying sizes covering 65 mouse tissues, including the glomerulus [16], and two compendia with microarray data from adult mouse tissues, including lung [17,18] (Figure 1a). miRNAs were scored for enrichment in glomerulus and lung and this formed the basis of our selection (Additional data file 2)
Summary
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. MicroRNAs (miRNAs) are short endogenous RNAs that regulate gene expression through translational repression of specific target mRNA transcripts. Maturation begins with trimming of the immediate transcribed product into a stem-loop structure (the pre-miRNA) by the nuclear enzyme Drosha This is followed by cleavage by the cytosolic enzyme Dicer into a short 19- to 25-bp double-stranded RNA [2]. Others, including let-7f, miR-27b [6], miR-221, and miR-222 [12], have been shown to modulate angiogenesis in vitro and overexpression or inhibition of miR-378 [13], the miR-17-92 cluster [14] and miR-296 [15] affects angiogenesis in mouse engrafted tumors Some of these studies show direct regulation of a target gene, but downstream mechanisms are in many cases unknown
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