Long Noncoding RNA MALAT1 Regulates Endothelial Cell Function and Vessel Growth

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.

miRNAs and lncRNAs in vascular injury and remodeling

“…Additionally, pharmacological inhibition of MALAT1 reduced blood flow recovery and capillary density after hindlimb ischemia by impairing the expression of various cell cycle regulators. These results suggest that knockdown of MALAT1 impairs the balance of endothelial cell from a proliferative to a migratory phenotype, and further reduces vascular growth [74].…”

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

“…Conversely, the progression into a more severe phenotype redirects the transcriptome toward pathways biologically related with mitochondrial dysfunction21, 22 and malignancy 4, 5, 10. In this respect, MALAT1 represents a remarkable functional and versatile molecule that modulates a myriad of signaling pathways, including cell cycle control,18 immune balance,23 and endothelial cell function and vessel growth 24. These phenomena, when present concurrently, escalate in complexity to entail cell proliferation and migration,25 apoptosis, fibrosis,26 and malignancy 27…”

Long Noncoding RNAs in Atherosclerosis

“…Katharina et al 51) found that MALAT1 silencing by siRNA or LNA GapmeRs induced a phenotype switch of the endothelial cells from a proliferation state to a promigratory state. This type of phenotype switch results in a block in vessel outgrowth cells and tissues such as SMCs, ECs, monocytederived macrophages, and RNA samples extracted from carotid and arterectomy 41) .…”