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      Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification

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          Abstract

          Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.

          Abstract

          New vessel formation relies on a tightly controlled switch in endothelial biology from proliferating to  specializing phenotypes. Here, Fang et al. elucidate the molecular mechanisms of this switch and show that the arterial shear activates a Notch-Cx37-p27 axis promoting endothelial cell cycle arrest and enabling arterial gene expression.

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          Most cited references47

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          Linking the Cell Cycle to Cell Fate Decisions.

          Pluripotent stem cells (PSCs) retain the ability to differentiate into a wide range of cell types while undergoing self-renewal. They also exhibit an unusual mode of cell cycle regulation, reflected by a cell cycle structure where G1 and G2 phases are truncated. When individual PSCs are exposed to specification cues, they activate developmental programs and remodel the cell cycle so that the length of G1 and overall cell division times increase. The response of individual stem cells to pro-differentiation signals is strikingly heterogeneous, resulting in asynchronous differentiation. Recent evidence indicates that this phenomenon is due to cell cycle-dependent mechanisms that restrict the initial activation of developmental genes to the G1 phase. This suggests a broad biological mechanism where multipotent cells are 'primed' to initiate cell fate decisions during their transition through G1. Here, I discuss mechanisms underpinning the commitment towards the differentiated state and its relation to the cell cycle.
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            Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation.

            Lymphatic valves are essential for efficient lymphatic transport, but the mechanisms of early lymphatic-valve morphogenesis and the role of biomechanical forces are not well understood. We found that the transcription factors PROX1 and FOXC2, highly expressed from the onset of valve formation, mediate segregation of lymphatic-valve-forming cells and cell mechanosensory responses to shear stress in vitro. Mechanistically, PROX1, FOXC2, and flow coordinately control expression of the gap junction protein connexin37 and activation of calcineurin/NFAT signaling. Connexin37 and calcineurin are required for the assembly and delimitation of lymphatic valve territory during development and for its postnatal maintenance. We propose a model in which regionally increased levels/activation states of transcription factors cooperate with mechanotransduction to induce a discrete cell-signaling pattern and morphogenetic event, such as formation of lymphatic valves. Our results also provide molecular insights into the role of endothelial cell identity in the regulation of vascular mechanotransduction. Copyright © 2012 Elsevier Inc. All rights reserved.
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              microRNA-mediated integration of haemodynamics and Vegf signaling during angiogenesis

              Within the circulatory system, blood flow regulates vascular remodeling1, stimulates blood stem cell formation2, and plays a role in the pathology of vascular disease3. During vertebrate embryogenesis, vascular patterning is initially guided by conserved genetic pathways that act prior to circulation4. Subsequently, endothelial cells must incorporate the mechanosensory stimulus of blood flow with these early signals to shape the embryonic vascular system4. However, few details are known about how these signals are integrated during development. To investigate this process, we focused on the aortic arch (AA) blood vessels, which are known to remodel in response to blood flow1. By using 2-photon imaging of live zebrafish embryos, we observe that flow is essential for angiogenesis during AA development. We further find that angiogenic sprouting of AA vessels requires a flow-induced genetic pathway in which the mechano-sensitive zinc finger transcription factor klf2a 5-7 induces expression of an endothelial-specific microRNA, mir-126, to activate Vegf signaling. Taken together, our work describes a novel genetic mechanism in which a microRNA facilitates integration of a physiological stimulus with growth factor signaling in endothelial cells to guide angiogenesis.
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                Author and article information

                Contributors
                karen.hirschi@yale.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                15 December 2017
                15 December 2017
                2017
                : 8
                : 2149
                Affiliations
                [1 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Medicine, , Yale University School of Medicine, ; 333 Cedar Street, New Haven, CT 06520 USA
                [2 ]ISNI 0000000419368710, GRID grid.47100.32, Yale Cardiovascular Research Center, , Yale University School of Medicine, ; 333 Cedar Street, New Haven, CT 06520 USA
                [3 ]ISNI 0000000419368710, GRID grid.47100.32, Vascular Biology and Therapeutics Program, , Yale University School of Medicine, ; 333 Cedar Street, New Haven, CT 06520 USA
                [4 ]ISNI 0000000419368710, GRID grid.47100.32, Yale Stem Cell Center, , Yale University School of Medicine, ; 333 Cedar Street, New Haven, CT 06520 USA
                [5 ]Computational Statistics and Bioinformatics Group, Advanced Artificial Intelligence Research Laboratory, WuXi NextCODE 55 Cambridge Parkway, 8th Floor, Cambridge, MA 02142 USA
                [6 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Genetics, , Yale University School of Medicine, ; 333 Cedar Street, New Haven, CT 06520 USA
                [7 ]Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, A-111, 25 Shattuck Street, Boston, MA 02115 USA
                [8 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Department of Biological Engineering, , Massachusetts Institute of Technology, ; 21 Ames Street #56-651, Cambridge, MA 02142 USA
                [9 ]ISNI 0000 0001 2168 186X, GRID grid.134563.6, Department of Physiology, , College of Medicine, The University of Arizona, ; 1501 N. Campbell Road, Tucson, AZ 85724 USA
                [10 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Cell Biology, , Yale University School of Medicine, ; 333 Cedar Street, New Haven, CT 06520 USA
                [11 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Biomedical Engineering, , Yale University School of Medicine, ; 333 Cedar Street, New Haven, CT 06520 USA
                Author information
                http://orcid.org/0000-0002-4516-0193
                http://orcid.org/0000-0002-2071-1243
                http://orcid.org/0000-0001-7116-0130
                Article
                1742
                10.1038/s41467-017-01742-7
                5732288
                29247167
                efb85c9f-dfe7-463b-b31a-7c03745a163c
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 November 2016
                : 13 October 2017
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