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      Lysyl oxidase‐like 2 is a regulator of angiogenesis through modulation of endothelial‐to‐mesenchymal transition

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          Abstract

          Lysyl oxidase‐like 2 (LOXL2) belongs to the family of lysyl oxidases, and as such promotes crosslinking of collagens and elastin by oxidative deamination of lysine residues. In endothelial cells (ECs), LOXL2 is involved in crosslinking and scaffolding of collagen IV. Additionally, several reports have shown a role for LOXL2 in other processes, including regulation of gene expression, tumor metastasis, and epithelial‐to‐mesenchymal transition (EMT). Here, we demonstrate an additional role for LOXL2 in the regulation of angiogenesis by modulation of endothelial‐to‐mesenchymal transition (EndMT). LOXL2 knockdown in ECs results in decreased migration and sprouting, and concordantly, LOXL2 overexpression leads to an increase in migration and sprouting, independent of its catalytic activity. Furthermore, LOXL2 knockdown resulted in a reduced expression of EndMT markers, and inhibition of transforming growth factor‐β (TGF‐β)‐mediated induction of EndMT. Interestingly, unlike in EMT, overexpression of LOXL2 alone is insufficient to induce EndMT. Further investigation revealed that LOXL2 expression regulates protein kinase B (PKB)/Akt and focal adhesion kinase (FAK) signaling, both pathways that have been implicated in the regulation of EMT. Altogether, our studies reveal a role for LOXL2 in angiogenesis through the modulation of EndMT in ECs, independent of its enzymatic crosslinking activity.

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          Most cited references 35

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          The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression.

          The Snail family of transcription factors has previously been implicated in the differentiation of epithelial cells into mesenchymal cells (epithelial-mesenchymal transitions) during embryonic development. Epithelial-mesenchymal transitions are also determinants of the progression of carcinomas, occurring concomitantly with the cellular acquisition of migratory properties following downregulation of expression of the adhesion protein E-cadherin. Here we show that mouse Snail is a strong repressor of transcription of the E-cadherin gene. Epithelial cells that ectopically express Snail adopt a fibroblastoid phenotype and acquire tumorigenic and invasive properties. Endogenous Snail protein is present in invasive mouse and human carcinoma cell lines and tumours in which E-cadherin expression has been lost. Therefore, the same molecules are used to trigger epithelial-mesenchymal transitions during embryonic development and in tumour progression. Snail may thus be considered as a marker for malignancy, opening up new avenues for the design of specific anti-invasive drugs.
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            Endothelial-to-mesenchymal transition contributes to cardiac fibrosis.

            Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-beta1 (TGF-beta1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.
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              Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways.

              Epithelial-mesenchymal transition (EMT) is an important process during development by which epithelial cells acquire mesenchymal, fibroblast-like properties and show reduced intercellular adhesion and increased motility. Accumulating evidence points to a critical role of EMT-like events during tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. Several oncogenic pathways (peptide growth factors, Src, Ras, Ets, integrin, Wnt/beta-catenin and Notch) induce EMT and a critical molecular event is the downregulation of the cell adhesion molecule E-cadherin. Recently, activation of the phosphatidylinositol 3' kinase (PI3K)/AKT axis is emerging as a central feature of EMT. In this review, we discuss the role of PI3K/AKT pathways in EMT during development and cancer with a focus on E-cadherin regulation. Interactions between PI3K/AKT and other EMT-inducing pathways are presented, along with a discussion of the therapeutic implications of modulating EMT in order to achieve cancer control.
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                Author and article information

                Contributors
                o.g.dejong-2@umcutrecht.nl
                Journal
                J Cell Physiol
                J. Cell. Physiol
                10.1002/(ISSN)1097-4652
                JCP
                Journal of Cellular Physiology
                John Wiley and Sons Inc. (Hoboken )
                0021-9541
                1097-4652
                01 November 2018
                July 2019
                : 234
                : 7 ( doiID: 10.1002/jcp.v234.7 )
                : 10260-10269
                Affiliations
                [ 1 ] Department of Nephrology and Hypertension University Medical Center Utrecht, Utrecht University Utrecht The Netherlands
                [ 2 ] Department of Physiology Anatomy and Genetics, University of Oxford Oxford United Kingdom
                [ 3 ] Laboratory Translational Oncology, Cancer Center, University Medical Center Utrecht Utrecht The Netherlands
                Author notes
                [* ] Correspondence Olivier G. de Jong, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Email: o.g.dejong-2@ 123456umcutrecht.nl

                [†]

                Marianne C. Verhaar and Bas W. M. van Balkom contributed equally to this work.

                Article
                JCP27695
                10.1002/jcp.27695
                6587725
                30387148
                © 2018 The Authors Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 5, Tables: 0, Pages: 10, Words: 5909
                Product
                Funding
                Funded by: Netherlands Institute for Regenerative Medicine
                Award ID: FES0908
                Funded by: Netherlands Organization for Scientific Research
                Award ID: Vidi 016.096.359
                Categories
                Original Research Article
                Original Research Articles
                Custom metadata
                2.0
                jcp27695
                July 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:21.06.2019

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