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      miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

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          Abstract

          Background

          Endothelial cells ( ECs) form blood vessels through angiogenesis that is regulated by coordination of vascular endothelial growth factor ( VEGF), Notch, transforming growth factor β, and other signals, but the detailed molecular mechanisms remain unclear.

          Methods and Results

          Small RNA sequencing initially identified miR‐342‐5p as a novel downstream molecule of Notch signaling in ECs. Reporter assay, quantitative reverse transcription polymerase chain reaction and Western blot analysis indicated that miR‐342‐5p targeted endoglin and modulated transforming growth factor β signaling by repressing SMAD1/5 phosphorylation in ECs. Transfection of miR‐342‐5p inhibited EC proliferation and lumen formation and reduced angiogenesis in vitro and in vivo, as assayed by using a fibrin beads–based sprouting assay, mouse aortic ring culture, and intravitreal injection of miR‐342‐5p agomir in P3 pups. Moreover, miR‐342‐5p promoted the migration of ECs, accompanied by reduced endothelial markers and increased mesenchymal markers, indicative of increased endothelial–mesenchymal transition. Transfection of endoglin at least partially reversed endothelial–mesenchymal transition induced by miR‐342‐5p. The expression of miR‐342‐5p was upregulated by transforming growth factor β, and inhibition of miR‐342‐5p attenuated the inhibitory effects of transforming growth factor β on lumen formation and sprouting by ECs. In addition, VEGF repressed miR‐342‐5p expression, and transfection of miR‐342‐5p repressed VEGFR2 and VEGFR3 expression and VEGF‐triggered Akt phosphorylation in ECs. miR‐342‐5p repressed angiogenesis in a laser‐induced choroidal neovascularization model in mice, highlighting its clinical potential.

          Conclusions

          miR‐342‐5p acts as a multifunctional angiogenic repressor mediating the effects and interaction among angiogenic pathways.

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          Most cited references33

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          Regulation of EMT by TGFβ in cancer.

          Transforming growth factor-β (TGFβ) suppresses tumor formation since it inhibits cell growth and promotes apoptosis. However, in advanced cancers TGFβ elicits tumor promoting effects through its ability to induce epithelial-mesenchymal transition (EMT) which enhances invasiveness and metastasis; in addition, TGFβ exerts tumor promoting effects on non-malignant cells of the tumor, including suppression of immune surveillance and stimulation of angiogenesis. TGFβ promotes EMT by transcriptional and posttranscriptional regulation of a group of transcription factors that suppresses epithelial features, such as expression of components of cell junctions and polarity complexes, and enhances mesenchymal features, such as production of matrix molecules and several cytokines and growth factors that stimulate cell migration. The EMT program has certain similarities with the stem cell program. Inducers and effectors of EMT are interesting targets for the development of improved diagnosis, prognosis and therapy of cancer. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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            Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis.

            Posttranscriptional gene regulation by microRNAs (miRNAs) is important for many aspects of development, homeostasis, and disease. Here, we show that reduction of endothelial miRNAs by cell-specific inactivation of Dicer, the terminal endonuclease responsible for the generation of miRNAs, reduces postnatal angiogenic response to a variety of stimuli, including exogenous VEGF, tumors, limb ischemia, and wound healing. Furthermore, VEGF regulated the expression of several miRNAs, including the up-regulation of components of the c-Myc oncogenic cluster miR-17-92. Transfection of endothelial cells with components of the miR-17-92 cluster, induced by VEGF treatment, rescued the induced expression of thrombospondin-1 and the defect in endothelial cell proliferation and morphogenesis initiated by the loss of Dicer. Thus, endothelial miRNAs regulate postnatal angiogenesis and VEGF induces the expression of miRNAs implicated in the regulation of an integrated angiogenic response.
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              Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis.

              The activin receptor-like kinase 1 (ALK1) is a type I receptor for transforming growth factor-beta (TGF-beta) family proteins. Expression of ALK1 in blood vessels and mutations of the ALK1 gene in human type II hereditary hemorrhagic telangiectasia patients suggest that ALK1 may have an important role during vascular development. To define the function of ALK1 during development, we inactivated the ALK1 gene in mice by gene targeting. The ALK1 homozygous embryos die at midgestation, exhibiting severe vascular abnormalities characterized by excessive fusion of capillary plexes into cavernous vessels and hyperdilation of large vessels. These vascular defects are associated with enhanced expression of angiogenic factors and proteases and are characterized by deficient differentiation and recruitment of vascular smooth muscle cells. The blood vessel defects in ALK1-deficient mice are reminiscent of mice lacking TGF-beta1, TGF-beta type II receptor (TbetaR-II), or endoglin, suggesting that ALK1 may mediate TGF-beta1 signal in endothelial cells. Consistent with this hypothesis, we demonstrate that ALK1 in endothelial cells binds to TGF-beta1 and TbetaR-II. Furthermore, the ALK1 signaling pathway can inhibit TGF-beta1-dependent transcriptional activation mediated by the known TGF-beta1 type I receptor, ALK5. Taken together, our results suggest that the balance between the ALK1 and ALK5 signaling pathways in endothelial cells plays a crucial role in determining vascular endothelial properties during angiogenesis.
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                Author and article information

                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                08 February 2016
                February 2016
                : 5
                : 2 ( doiID: 10.1002/jah3.2016.5.issue-2 )
                : e003042
                Affiliations
                [ 1 ] State Key Laboratory of Cancer Biology Department of Medical Genetics and Developmental Biology Xijing HospitalFourth Military Medical University Xi'anChina
                [ 2 ] Department of Respiratory Medicine Xijing HospitalFourth Military Medical University Xi'anChina
                [ 3 ] Department of Ophthalmology Xijing HospitalFourth Military Medical University Xi'anChina
                [ 4 ] Department of Cardiovascular Surgery Xijing HospitalFourth Military Medical University Xi'anChina
                Author notes
                [*] [* ] Correspondence to: Hua Han, PhD, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang‐Le Xi Street #17, Xi'an 710032, China. E‐mail: huahan@ 123456fmmu.edu.cn

                [†]

                Mr Yan, Ms Cao, Dr Liang, and Ms Wang contributed equally in this study.

                Article
                JAH31326
                10.1161/JAHA.115.003042
                4802463
                26857067
                f6c92bbe-7153-4a4e-bdb1-7d8935d40a65
                © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 12 December 2015
                : 07 January 2016
                Page count
                Pages: 15
                Funding
                Funded by: Ministry of Science and Technology
                Award ID: 2015CB553702
                Funded by: National Natural Science Foundation of China
                Award ID: 91339115
                Award ID: 31370769
                Award ID: 81200707
                Award ID: 31301194
                Award ID: 31071291
                Award ID: 81470416
                Award ID: 81370512
                Categories
                Original Research
                Original Research
                Molecular Cardiology
                Custom metadata
                2.0
                jah31326
                February 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.4 mode:remove_FC converted:03.03.2016

                Cardiovascular Medicine
                angiogenesis,endothelial cell,endothelial cell differentiation,microrna,notch,vascular endothelial growth factor,endothelium/vascular type/nitric oxide,developmental biology,basic science research

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