Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth

Item Type:	Article
Title:	Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth
Creators Name:	Michalik, K.M. and You, X. and Manavski, Y. and Doddaballapur, A. and Zoernig, M. and Braun, T. and John, D. and Ponomareva, Y. and Chen, W. and Uchida, S. and Boon, R.A. and Dimmeler, S.
Abstract:	RATIONALE: The human genome harbors a large number of sequences encoding for RNAs that are not translated but control cellular functions by distinct mechanisms. The expression and function of the longer transcripts namely the long noncoding RNAs in the vasculature are largely unknown. OBJECTIVE: Here, we characterized the expression of long noncoding RNAs in human endothelial cells and elucidated the function of the highly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). METHODS AND RESULTS: Endothelial cells of different origin express relative high levels of the conserved long noncoding RNAs MALAT1, taurine upregulated gene 1 (TUG1), maternally expressed 3 (MEG3), linc00657, and linc00493. MALAT1 was significantly increased by hypoxia and controls a phenotypic switch in endothelial cells. Silencing of MALAT1 by small interfering RNAs or GapmeRs induced a promigratory response and increased basal sprouting and migration, whereas proliferation of endothelial cells was inhibited. When angiogenesis was further stimulated by vascular endothelial growth factor, MALAT1 small interfering RNAs induced discontinuous sprouts indicative of defective proliferation of stalk cells. In vivo studies confirmed that genetic ablation of MALAT1 inhibited proliferation of endothelial cells and reduced neonatal retina vascularization. Pharmacological inhibition of MALAT1 by GapmeRs reduced blood flow recovery and capillary density after hindlimb ischemia. Gene expression profiling followed by confirmatory quantitative reverse transcriptase-polymerase chain reaction demonstrated that silencing of MALAT1 impaired the expression of various cell cycle regulators. CONCLUSIONS: Silencing of MALAT1 tips the balance from a proliferative to a migratory endothelial cell phenotype in vitro, and its genetic deletion or pharmacological inhibition reduces vascular growth in vivo.
Keywords:	Angiogenesis Effect, Endothelium, Ischemia, Neovascularization Inhibitors, Long Noncoding RNA, Animals, Mice
Source:	Circulation Research
ISSN:	0009-7330
Publisher:	American Heart Association
Volume:	114
Number:	9
Page Range:	1389-1397
Date:	25 April 2014
Official Publication:	https://doi.org/10.1161/CIRCRESAHA.114.303265
PubMed:	View item in PubMed

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