Long Non-Coding RNA Malat1 Regulates Angiogenesis in Hindlimb Ischemia

0301 basic medicine vascular endothelial cells Neovascularization, Physiologic Article angiogenesis Mice 03 medical and health sciences Cell Movement Ischemia Animals Gene Silencing Muscle, Skeletal Cell Proliferation 0303 health sciences hindlimb ischemia long non-coding RNA <i>Malat1</i> Endothelial Cells Vascular Endothelial Growth Factor Receptor-2 Hindlimb VEGFR2 Regional Blood Flow Microvessels RNA, Long Noncoding Gene Deletion Protein Binding
DOI: 10.3390/ijms19061723 Publication Date: 2018-06-11T15:01:01Z
ABSTRACT
Angiogenesis is a complex process that depends on the delicate regulation of gene expression. Dysregulation of transcription during angiogenesis often leads to various human diseases. Emerging evidence has recently begun to show that long non-coding RNAs (lncRNAs) may mediate angiogenesis in both physiological and pathological conditions; concurrently, underlying molecular mechanisms are largely unexplored. Previously, our lab identified metastasis associates lung adenocarcinoma transcript 1 (Malat1) as an oxygen-glucose deprivation (OGD)-responsive endothelial lncRNA. Here we reported that genetic deficiency of Malat1 leads to reduced blood vessel formation and local blood flow perfusion in mouse hind limbs at one to four weeks after hindlimb ischemia. Malat1 and vascular endothelial growth factor receptor 2 (VEGFR2) levels were found to be increased in both cultured mouse primary skeletal muscle microvascular endothelial cells (SMMECs) after 16 h OGD followed by 24 h reperfusion and in mouse gastrocnemius muscle that underwent hindlimb ischemia followed by 28 days of reperfusion. Moreover, Malat1 silencing by locked nucleic acid (LNA)-GapmeRs significantly reduced tube formation, cell migration, and cell proliferation in SMMEC cultures. Mechanistically, RNA subcellular isolation and RNA-immunoprecipitation experiments demonstrate that Malat1 directly targets VEGFR2 to facilitate angiogenesis. The results suggest that Malat1 regulates cell-autonomous angiogenesis through direct regulation of VEGFR2.
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