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  • 1.
    Bentley, Katie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Computat Biol Lab, Boston, MA USA..
    Chakravartula, Shilpa
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Computat Biol Lab, Boston, MA USA..
    The temporal basis of angiogenesis2017In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 372, no 1720, p. 1-11, article id 20150522Article in journal (Refereed)
    Abstract [en]

    The process of new blood vessel growth (angiogenesis) is highly dynamic, involving complex coordination of multiple cell types. Though the process must carefully unfold over time to generate functional, well-adapted branching networks, we seldom hear about the time-based properties of angiogenesis, despite timing being central to other areas of biology. Here, we present a novel, time-based formulation of endothelial cell behaviour during angiogenesis and discuss a flurry of our recent, integrated in silico/in vivo studies, put in context to the wider literature, which demonstrate that tissue conditions can locally adapt the timing of collective cell behaviours/decisions to grow different vascular network architectures. A growing array of seemingly unrelated 'temporal regulators' have recently been uncovered, including tissue derived factors (e.g. semaphorins or the high levels of VEGF found in cancer) and cellular processes (e.g. asymmetric cell division or filopodia extension) that act to alter the speed of cellular decisions to migrate. We will argue that 'temporal adaptation' provides a novel account of organ/disease-specific vascular morphology and reveals 'timing' as a new target for therapeutics. We therefore propose and explain a conceptual shift towards a 'temporal adaptation' perspective in vascular biology, and indeed other areas of biology where timing remains elusive. This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'.

  • 2.
    Costa, Guilherme
    et al.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Harrington, Kyle I.
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Lovegrove, Holly E.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Page, Donna J.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Chakravartula, Shilpa
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Herbert, Shane P.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Asymmetric division coordinates collective cell migration in angiogenesis2016In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 18, no 12, p. 1292-+Article in journal (Refereed)
    Abstract [en]

    The asymmetric division of stem or progenitor cells generates daughters with distinct fates and regulates cell diversity during tissue morphogenesis. However, roles for asymmetric division in other more dynamic morphogenetic processes, such as cell migration, have not previously been described. Here we combine zebrafish in vivo experimental and computational approaches to reveal that heterogeneity introduced by asymmetric division generates multicellular polarity that drives coordinated collective cell migration in angiogenesis. We find that asymmetric positioning of the mitotic spindle during endothelial tip cell division generates daughters of distinct size with discrete 'tip' or 'stalk' thresholds of pro-migratory Vegfr signalling. Consequently, post-mitotic Vegfr asymmetry drives Dll4/Notch-independent self-organization of daughters into leading tip or trailing stalk cells, and disruption of asymmetry randomizes daughter tip/stalk selection. Thus, asymmetric division seamlessly integrates cell proliferation with collective migration, and, as such, may facilitate growth of other collectively migrating tissues during development, regeneration and cancer invasion.

  • 3.
    Gomez-Escudero, Jesus
    et al.
    CNIC, Vasc Pathophysiol, Melchor Fernandez Almagro 3, Madrid 28029, Spain;Queen Marys Univ London, Johns Vane Ctr, Barts Canc Inst, Tumour Biol Dept, Charterhouse Sq, London EC1M 6BQ, England.
    Clemente, Cristina
    CNIC, Vasc Pathophysiol, Melchor Fernandez Almagro 3, Madrid 28029, Spain;CSIC, CIB, Ramiro de Maeztu 9, Madrid 28040, Spain.
    Garcia-Weber, Diego
    Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, E-28049 Madrid, Spain.
    Acin-Perez, Rebeca
    CNIC, Myocardial Pathol Areas, Melchor Fernandez Almagro 3, Madrid 28029, Spain.
    Millan, Jaime
    Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, E-28049 Madrid, Spain.
    Enriquez, Jose A.
    CNIC, Myocardial Pathol Areas, Melchor Fernandez Almagro 3, Madrid 28029, Spain.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Computat Biol Lab, Boston, MA 02115 USA.
    Carmeliet, Peter
    VIB, Ctr Canc Biol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium;Univ Leuven, Lab Angiogenesis & Vasc Metab, Ctr Canc Biol, Dept Oncol, B-3000 Leuven, Belgium;Sun Yat Sen Univ, Zhongsan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou, Guangdong, Peoples R China.
    Arroyo, Alicia G.
    CNIC, Vasc Pathophysiol, Melchor Fernandez Almagro 3, Madrid 28029, Spain;CSIC, CIB, Ramiro de Maeztu 9, Madrid 28040, Spain.
    PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 15022Article in journal (Refereed)
    Abstract [en]

    Angiogenesis, the formation of new blood vessels from pre-existing ones, occurs in pathophysiological contexts such as wound healing, cancer, and chronic inflammatory disease. During sprouting angiogenesis, endothelial tip and stalk cells coordinately remodel their cell-cell junctions to allow collective migration and extension of the sprout while maintaining barrier integrity. All these processes require energy, and the predominant ATP generation route in endothelial cells is glycolysis. However, it remains unclear how ATP reaches the plasma membrane and intercellular junctions. In this study, we demonstrate that the glycolytic enzyme pyruvate kinase 2 (PKM2) is required for sprouting angiogenesis in vitro and in vivo through the regulation of endothelial cell-junction dynamics and collective migration. We show that PKM2-silencing decreases ATP required for proper VE-cadherin internalization/traffic at endothelial cell-cell junctions. Our study provides fresh insight into the role of ATP subcellular compartmentalization in endothelial cells during angiogenesis. Since manipulation of EC glycolysis constitutes a potential therapeutic intervention route, particularly in tumors and chronic inflammatory disease, these findings may help to refine the targeting of endothelial glycolytic activity in disease.

  • 4.
    Laviña, Bàrbara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Castro, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Niaudet, Colin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Bert, Cruys
    Peter, Carmeliet
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. 4Computational Biology Laboratory, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
    Cord, Brakebusch
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations: Cdc42 and vascular malformationsManuscript (preprint) (Other academic)
  • 5.
    Laviña, Bàrbara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Castro, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Niaudet, Colin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Cruys, Bert
    VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Leuven, Belgium; Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium.
    Álvarez-Aznar, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Carmeliet, Peter
    VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Leuven, Belgium; Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Computat Biol Lab, Boston, MA USA.
    Brakebusch, Cord
    Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge, ICMC, Stockholm, Sweden.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 13, article id UNSP dev161182Article in journal (Refereed)
    Abstract [en]

    Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.

  • 6.
    Li, Xiujuan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Padhan, Narendra
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala Univ, Sci Life Lab, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Sjöström, Elisabet O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Sci Life Lab, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Roche, Francis P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Testini, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Honkura, Naoki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sainz-Jaspeado, Miguel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gordon, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, 330 Brookline Ave, Boston, MA 02215 USA..
    Philippides, Andrew
    Univ Sussex, Ctr Computat Neurosci & Robot, Chichester 1 CI 104, Brighton BN1 9RH, E Sussex, England..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. IFOM IEO Campus, Via Adamello 16, I-20139 Milan, Italy..
    Stan, Radu V.
    Dartmouth Coll, Dept Pathol, Geisel Sch Med Dartmouth, Lebanon, NH 03756 USA..
    Vestweber, Dietmar
    Max Planck Inst Mol Biomed, Dept Vasc Cell Biol, Rontgenstr 20, D-48149 Munster, Germany..
    Ballmer-Hofer, Kurt
    Paul Scherrer Inst, Biomol Res, Mol Cell Biol, CH-5232 Villigen, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Pietras, Kristian
    Lund Univ, Medicon Village, Translat Canc Res, Bldg 404-A3, S-22381 Lund, Sweden..
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11017Article in journal (Refereed)
    Abstract [en]

    The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

  • 7.
    Miloudi, Khalil
    et al.
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada;McGill Univ, Dept Neurol Neurosurg, Montreal, PQ H3A 2B4, Canada.
    Oubaha, Malika
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada.
    Menard, Catherine
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada.
    Dejda, Agnieszka
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada.
    Guber, Vera
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada.
    Cagnone, Gael
    Ctr Hosp Univ Ste Justine, Res Ctr, Dept Pediat, Montreal, PQ H1T 2M4, Canada;Ctr Hosp Univ Ste Justine, Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada;Ctr Hosp Univ Ste Justine, Res Ctr, Dept Pharmacol, Montreal, PQ H1T 2M4, Canada;Univ Montreal, Dept Pharmacol & Physiol, Fac Med, Montreal, PQ H3C 3J7, Canada.
    Wilson, Ariel M.
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada.
    Tetreault, Nicolas
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada.
    Mawambo, Gaelle
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada.
    Binet, Francois
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada.
    Chidiac, Rony
    Univ Montreal, Dept Pharmacol & Physiol, Fac Med, Montreal, PQ H3C 3J7, Canada.
    Delisle, Chantal
    Univ Montreal, Dept Pharmacol & Physiol, Fac Med, Montreal, PQ H3C 3J7, Canada.
    Buscarlet, Manuel
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada.
    Cerani, Agustin
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada.
    Crespo-Garcia, Sergio
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Rezende, Flavio
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada.
    Joyal, Jean-Sebastien
    Ctr Hosp Univ Ste Justine, Res Ctr, Dept Pediat, Montreal, PQ H1T 2M4, Canada;Ctr Hosp Univ Ste Justine, Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada;Ctr Hosp Univ Ste Justine, Res Ctr, Dept Pharmacol, Montreal, PQ H1T 2M4, Canada.
    Mallette, Frederick A.
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem & Mol Med, Montreal, PQ H1T 2M4, Canada;Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Med, Montreal, PQ H1T 2M4, Canada.
    Gratton, Jean-Philippe
    Univ Montreal, Dept Pharmacol & Physiol, Fac Med, Montreal, PQ H3C 3J7, Canada.
    Larrivee, Bruno
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada.
    Sapieha, Przemyslaw
    Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada;McGill Univ, Dept Neurol Neurosurg, Montreal, PQ H3A 2B4, Canada.
    NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 10, p. 4538-4547Article in journal (Refereed)
    Abstract [en]

    Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from beta-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.

  • 8.
    Page, Donna J.
    et al.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England;Manchester Metropolitan Univ, Sch Healthcare Sci, Manchester M1 5GD, Lancs, England.
    Thuret, Raphael
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England.
    Venkatraman, Lakshmi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Boston Univ, Biomed Engn Dept, 610 Commonwealth Ave, Boston, MA 02215 USA.
    Takahashi, Tokiharu
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Boston Univ, Biomed Engn Dept, 610 Commonwealth Ave, Boston, MA 02215 USA;Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02215 USA;Francis Crick Inst, Cellular Adapt Behav Lab, Midland Rd, London NW1 1AT, England;Kings Coll London, Fac Nat & Math Sci, Dept Informat, Strand Campus, London WC2B 4BG, England.
    Herbert, Shane P.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England.
    Positive Feedback Defines the Timing, Magnitude, and Robustness of Angiogenesis2019In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 27, no 11, p. 3139-3151.e5Article in journal (Refereed)
    Abstract [en]

    Angiogenesis is driven by the coordinated collective branching of specialized leading "tip" and trailing "stalk" endothelial cells (ECs). While Notch-regulated negative feedback suppresses excessive tip selection, roles for positive feedback in EC identity decisions remain unexplored. Here, by integrating computational modeling with in vivo experimentation, we reveal that positive feedback critically modulates the magnitude, timing, and robustness of angiogenic responses. In silico modeling predicts that positivefeedback-mediated amplification of VEGF signaling generates an ultrasensitive bistable switch that underpins quick and robust tip-stalk decisions. In agreement, we define a positive-feedback loop exhibiting these properties in vivo, whereby Vegf-induced expression of the atypical tetraspanin, tm4sf18, amplifies Vegf signaling to dictate the speed and robustness of EC selection for angiogenesis. Consequently, tm4sf18 mutant zebrafish select fewer motile ECs and exhibit stunted hypocellular vessels with unstable tip identity that is severely perturbed by even subtle Vegfr attenuation. Hence, positive feedback spatiot-emporally shapes the angiogenic switch to ultimately modulate vascular network topology.

  • 9.
    Venkatraman, Lakshmi
    et al.
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02115 USA..
    Regan, Erzsebet Ravasz
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02115 USA.;Coll Wooster, Dept Biochem & Mol Biol, Wooster, OH 44691 USA..
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02115 USA..
    Time to Decide?: Dynamical Analysis Predicts Partial Tip/Stalk Patterning States Arise during Angiogenesis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0166489Article in journal (Refereed)
    Abstract [en]

    Angiogenesis is a highly dynamic morphogenesis process; however, surprisingly little is known about the timing of the different molecular processes involved. Although the role of the VEGF-notch-DLL4 signaling pathway has been established as essential for tip/stalk cell competition during sprouting, the speed and dynamic properties of the underlying process at the individual cell level has not been fully elucidated. In this study, using mathematical modeling we investigate how specific, biologically meaningful, local conditions around and within an individual cell can influence their unique tip/stalk phenotype switching kinetics. To this end we constructed an ordinary differential equation model of VEGF-notch-DLL4 signaling in a system of two, coupled endothelial cells (EC). Our studies reveal that at any given point in an angiogenic vessel the time it takes a cell to decide to take on a tip or stalk phenotype may be drastically different, and this asynchrony of tip/stalk cell decisions along vessels itself acts to speed up later competitions. We unexpectedly uncover intermediate "partial" yet stable states lying between the tip and stalk cell fates, and identify that internal cellular factors, such as NAD-dependent deacetylase sirtuin-1 (Sirt1) and Lunatic fringe 1 (Lfng1), can specifically determine the length of time a cell spends in these newly identified partial tip/stalk states. Importantly, the model predicts that these partial EC states can arise during normal angiogenesis, in particular during cell rearrangement in sprouts, providing a novel two-stage mechanism for rapid adaptive behavior to the cells highly dynamic environment. Overall, this study demonstrates that different factors (both internal and external to EC) can be used to modulate the speed of tip/stalk decisions, opening up new opportunities and challenges for future biological experiments and therapeutic targeting to manipulate vascular network topology, and our basic understanding of developmental/pathological angiogenesis.

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  • asciidoc
  • rtf