Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth

Katharina M. Michalik, Xintian You, Yosif Manavski, Anuradha Doddaballapur, Martin Zörnig, Thomas Braun, David John, Yuliya Ponomareva, Wei Chen, Shizuka Uchida, Reinier A. Boon, Stefanie Dimmeler*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1389-1397
Number of pages9
JournalCirculation Research
Volume114
Issue number9
DOIs
Publication statusPublished - 25 Apr 2014

Cite this

Michalik, K. M., You, X., Manavski, Y., Doddaballapur, A., Zörnig, M., Braun, T., ... Dimmeler, S. (2014). Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circulation Research, 114(9), 1389-1397. https://doi.org/10.1161/CIRCRESAHA.114.303265