The Long Noncoding RNA MALAT1 Regulates Endothelial Cell Function and Vessel Growth
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 non-coding RNAs (lncRNAs) in the vasculature is largely unknown.
Objective: Here, we characterized the expression of lncRNAs in human endothelial cells and elucidated the function of the highly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1; also known as MALAT-1 or NEAT2).
Methods and Results: Endothelial cells of different origin express high levels of the conserved lncRNAs MALAT1, TUG1, MEG3, linc00657 and linc00493. MALAT1 was significantly increased by hypoxia and controls a phenotypic switch in endothelial cells. Silencing of MALAT1 by siRNAs or GapmeRs induced a pro-migratory response and increased basal sprouting and migration, whereas proliferation of endothelial cells was inhibited. When angiogenesis was further stimulated by VEGF, MALAT1 siRNAs 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 hind limb ischemia. Gene expression profiling followed by confirmatory qRT-PCR 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.
- Received December 18, 2013.
- Revision received March 5, 2014.
- Accepted March 6, 2014.