The original version of this Article contained errors in Fig. 8. In panel a, the labels 'VEGF', 'Notch', 'p21', and 'P-ERK' were inadvertently omitted. This has been corrected in the PDF and HTML versions of the Article.
Appropriate therapeutic modulation of endothelial proliferation and sprouting is essential for the effective inhibition of angiogenesis in cancer or its induction in cardiovascular disease. The current view is that an increase in growth factor concentration, and the resulting mitogenic activity, increases both endothelial proliferation and sprouting. Here, we modulate mitogenic stimuli in different vascular contexts by interfering with the function of the VEGF and Notch signalling pathways at high spatiotemporal resolution in vivo. Contrary to the prevailing view, our results indicate that high mitogenic stimulation induced by VEGF, or Notch inhibition, arrests the proliferation of angiogenic vessels. This is due to the existence of a bell-shaped dose-response to VEGF and MAPK activity that is counteracted by Notch and p21, determining whether endothelial cells sprout, proliferate, or become quiescent. The identified mechanism should be considered to achieve optimal therapeutic modulation of angiogenesis.
Endothelium, Vascular/drug effects , Mitogens/pharmacology , Neovascularization, Pathologic/drug therapy , Signal Transduction/drug effects , Animals , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Endothelium, Vascular/pathology , Human Umbilical Vein Endothelial Cells , Humans , Mice , Mice, Knockout , Neovascularization, Pathologic/pathology , Receptors, Notch/antagonists & inhibitors , Receptors, Notch/metabolism , Retina , Retinal Vessels , Signal Transduction/genetics , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolism
SIGNIFICANCE: Adenosine deamination in transcriptome results in the formation of inosine, a process that is called A-to-I RNA editing. Adenosine deamination is one of the more than 140 described RNA modifications. A-to-I RNA editing is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes and is essential for life. Recent Advances: Accumulating evidence supports a critical role of RNA editing in all aspects of RNA metabolism, including mRNA stability, splicing, nuclear export, and localization, as well as in recoding of proteins. These advances have significantly enhanced the understanding of mechanisms involved in development and in homeostasis. Furthermore, recent studies have indicated that RNA editing may be critically involved in cancer, aging, neurological, autoimmune, or cardiovascular diseases. CRITICAL ISSUES: This review summarizes recent and significant achievements in the field of A-to-I RNA editing and discusses the importance and translational value of this RNA modification for gene expression, cellular, and organ function, as well as for disease development. FUTURE DIRECTIONS: Elucidation of the exact RNA editing-dependent mechanisms in a single-nucleotide level may pave the path toward the development of novel therapeutic strategies focusing on modulation of ADAR function in the disease context. Antioxid. Redox Signal. 29, 846-863.
Adenosine/genetics , Disease/genetics , Inosine/genetics , RNA Editing/genetics , RNA/genetics , Adenosine/metabolism , Animals , Deamination , Homeostasis/genetics , Humans , Inosine/metabolism , RNA/metabolism
Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells. The 3' untranslated region (3' UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx+ regions, which form a long stem-loop structure that is recognized by ADAR1 as a substrate for editing. RNA editing enables the recruitment of the stabilizing RNA-binding protein human antigen R (HuR; encoded by ELAVL1) to the 3' UTR of the CTSS transcript, thereby controlling CTSS mRNA stability and expression. In endothelial cells, ADAR1 overexpression or treatment of cells with hypoxia or with the inflammatory cytokines interferon-γ and tumor-necrosis-factor-α induces CTSS RNA editing and consequently increases cathepsin S expression. ADAR1 levels and the extent of CTSS RNA editing are associated with changes in cathepsin S levels in patients with atherosclerotic vascular diseases, including subclinical atherosclerosis, coronary artery disease, aortic aneurysms and advanced carotid atherosclerotic disease. These results reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases.
Adenosine Deaminase/genetics , Atherosclerosis/genetics , Cathepsins/genetics , ELAV-Like Protein 1/genetics , RNA Editing/genetics , RNA, Messenger/metabolism , RNA-Binding Proteins/genetics , 3' Untranslated Regions , Adenosine/metabolism , Adult , Aged , Aged, 80 and over , Aortic Aneurysm/genetics , Carotid Artery Diseases/genetics , Coronary Artery Disease/genetics , Female , Fluorescent Antibody Technique , Gene Expression Regulation , Gene Knock-In Techniques , Gene Knockdown Techniques , High-Throughput Nucleotide Sequencing , Human Umbilical Vein Endothelial Cells , Humans , Hypoxia/genetics , Immunoblotting , Inosine/metabolism , Interferon-gamma/pharmacology , Male , Middle Aged , RNA Editing/drug effects , RNA Processing, Post-Transcriptional/drug effects , RNA Processing, Post-Transcriptional/genetics , Real-Time Polymerase Chain Reaction , Sequence Analysis, RNA , Tumor Necrosis Factor-alpha/pharmacology
