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Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis

Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis

Nature volume 445, pages 776–780 (2007)Cite this article

Abstract

In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A1,2. VEGF-A is also essential for the induction of endothelial tip cells2, but it is not known how single tip cells are selected to lead each vessel sprout, and how tip-cell numbers are determined. Here we present evidence that delta-like 4 (Dll4)–Notch1 signalling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in the mouse retina. We show that inhibition of Notch signalling using γ-secretase inhibitors, genetic inactivation of one allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1, all promote increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 peptide leads to fewer tip cells and vessel branches. Dll4 and reporters of Notch signalling are distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assume tip-cell characteristics. Together, our results suggest that Dll4–Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. This model offers an explanation for the dose-dependency and haploinsufficiency of the Dll4 gene3,4,5, and indicates that modulators of Dll4 or Notch signalling, such as γ-secretase inhibitors developed for Alzheimer’s disease, might find usage as pharmacological regulators of angiogenesis.

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  1. Ruhrberg, C. et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16, 2684–2698 (2002)

    Article  CAS  Google Scholar 

  2. Gerhardt, H. et al. VEGF guides angiogenic sprouting utilizing endothelial tip-cell filopodia. J. Cell Biol. 161, 1163–1177 (2003)

    Article  CAS  Google Scholar 

  3. Gale, N. W. et al. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc. Natl Acad. Sci. USA 101, 15949–15954 (2004)

    Article  ADS  CAS  Google Scholar 

  4. Krebs, L. T. et al. Haploinsufficienct lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev. 18, 2469–2473 (2004)

    Article  CAS  Google Scholar 

  5. Duarte, A. et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev. 18, 2474–2478 (2004)

    Article  CAS  Google Scholar 

  6. Uv, A., Cantera, R. & Samakovlis, C. Drosophila tracheal morphogenesis: intricate cellular solutions to basic plumbing problems. Trends Cell Biol. 13, 301–309 (2003)

    Article  CAS  Google Scholar 

  7. Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005)

    Article  ADS  CAS  Google Scholar 

  8. Lu, X. et al. The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432, 179–186 (2004)

    Article  ADS  CAS  Google Scholar 

  9. Torres-Vazquez, J. et al. Semaphorin-plexin signaling guides patterning of the developing vasculature. Dev. Cell 7, 117–123 (2004)

    Article  CAS  Google Scholar 

  10. Llimargas, M. The Notch pathway helps to pattern the tips of the Drosophila tracheal branches by selecting cell fates. Development 126, 2355–2364 (1999)

    CAS  PubMed  Google Scholar 

  11. Steneberg, P., Hemphala, J. & Samakovlis, C. Dpp and Notch specify the fusion cell fate in the dorsal branches of the Drosophila trachea. Mech. Dev. 87, 153–163 (1999)

    Article  CAS  Google Scholar 

  12. Ghabrial, A. S. & Krasnow, M. A. Social interactions among epithelial cells during tracheal branching morphogenesis. Nature 441, 746–749 (2006)

    Article  ADS  CAS  Google Scholar 

  13. Shawber, C. J. & Kitajewski, J. Notch function in the vasculature: Insights from zebrafish, mouse and man. Bioessays 26, 225–234 (2004)

    Article  CAS  Google Scholar 

  14. Dovey, H. F. et al. Functional γ-secretase inhibitors reduce β-amyloid peptide levels in brain. J. Neurochem. 76, 173–181 (2001)

    Article  CAS  Google Scholar 

  15. Searfoss, G. H. et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor. J. Biol. Chem. 278, 46107–46116 (2003)

    Article  CAS  Google Scholar 

  16. van Es, J. H. et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005)

    Article  ADS  CAS  Google Scholar 

  17. Kopan, R. & Ilagan, M. X. G. γ-secretases: proteasome of the membrane? Nature Rev. Mol. Cell Biol. 5, 499–504 (2004)

    Article  CAS  Google Scholar 

  18. Claxton, S. & Fruttiger, M. Periodic Delta-like 4 expression in developing retinal arteries. Gene Expr. Patterns 5, 123–127 (2004)

    Article  CAS  Google Scholar 

  19. Shutter, J. R. et al. Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev. 14, 1313–1318 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Lawson, N. D. et al. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128, 3675–3683 (2001)

    CAS  PubMed  Google Scholar 

  21. Domenga, V. et al. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 18, 2730–2735 (2004)

    Article  CAS  Google Scholar 

  22. Krebs, L. T. et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 14, 1343–1352 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Limbourg, F. P. et al. Essential role of endothelial Notch1 in angiogenesis. Circulation 111, 1826–1832 (2005)

    Article  CAS  Google Scholar 

  24. Monvoisin, A. et al. VE-cadherin-CreERT2 transgenic mouse: A model for inducible recombination in the endothelium. Dev. Dyn. 235, 3413–3422 (2006)

    Article  CAS  Google Scholar 

  25. Wolfer, A. et al. Inactivation of Notch1 in immature thymocytes does not perturb CD4 or CD8 T cell development. Nature Immunol. 2, 235–241 (2001)

    Article  CAS  Google Scholar 

  26. Duncan, A. W. et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nature Immunol. 6, 314–322 (2005)

    Article  CAS  Google Scholar 

  27. Itoh, M. et al. Mind Bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev. Cell 4, 67–82 (2003)

    Article  CAS  Google Scholar 

  28. Weijzen, S. et al. The notch ligand Jagged-1 is able to induce maturation of monocyte-derived human dendritic cells. J. Immunol. 169, 4273–4278 (2002)

    Article  CAS  Google Scholar 

  29. Grunstein, J., Masbad, J. J., Hickey, R., Giordano, F. & Johnson, R. S. Isoforms of vascular endothelial growth factor act in a coordinate fashion to recruit and expand tumor vasculature. Mol. Cell. Biol. 20, 7282–7291 (2000)

    Article  CAS  Google Scholar 

  30. Ferrara, N. Vascular endothelial growth factor: Basic science and clinical progress. Endocr. Rev. 25, 581–611 (2004)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank F. Radke for providing Notch1floxed/floxed mice. Support from the following foundations and granting agencies is acknowledged: Swedish Cancer Society, Association for International Cancer Research, European Union, the Novo Nordisk, Strategic Research, Söderberg, Hedlund, Wallenberg and Inga-Britt and Arne Lundberg Foundations (to C.B.); National Institutes of Health (US, NIH) and JH (USPHS National Research Service Award) (to L.I.-A.). H.G., L.-K.P. and P.L. are supported by Cancer Research UK. We acknowledge the Swegene Centre for Cellular Imaging at Gothenburg University for the use of imaging equipment, and the Light Microscopy Service and Peptide Synthesis Laboratory, London Research Institute (Cancer Research UK) for technical assistance.

Author information Author notes

  1. Per Lindblom, Ann-Katrin Nilsson & Linda Karlsson

    Present address: Present addresses: Molecular Toxicology, Safety Assessment, AstraZeneca R&D, SE-151 85 Södertälje, Sweden (P.L.); Stem Cell Center, BMC B10, Klinikg. 26, Lund University, SE-221 84 Lund, Sweden (A.-K.N.); Department of Physiology, Göteborg University, P.O. Box 434, SE-405 30 Göteborg, Sweden (L.K.).,

  2. Mattias Kalén, Holger Gerhardt and Christer Betsholtz: These authors contributed equally to this work.

Authors and Affiliations

  1. AngioGenetics Sweden AB, Scheeles väg 2, SE-171 77 Stockholm, Sweden,

    Mats Hellström, Elisabet Wallgard, Ann-Katrin Nilsson, Linda Karlsson & Mattias Kalén

  2. Department of Medical Biochemistry and Biophysics, Division of Matrix Biology, and,

    Mats Hellström, Elisabet Wallgard, Mattias Kalén & Christer Betsholtz

  3. Department of Medicine, Karolinska Institutet, SE 171 77 Stockholm, Sweden,

    Christer Betsholtz

  4. Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK,

    Li-Kun Phng, Per Lindblom & Holger Gerhardt

  5. Department of Molecular, Cell and Developmental Biology and Molecular Biology Institute, UCLA, Los Angeles, California 90095, USA,

    Jennifer J. Hofmann, Jackelyn Alva & M. Luisa Iruela-Arispe

  6. Program for Developmental Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada,

    Leigh Coultas & Janet Rossant

  7. Neurology, Neuroscience and Oncology, Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland 21205, USA,

    Nicholas Gaiano & Keejung Yoon

Authors
  1. Mats Hellström
  2. Li-Kun Phng
  3. Jennifer J. Hofmann
  4. Elisabet Wallgard
  5. Leigh Coultas
  6. Per Lindblom
  7. Jackelyn Alva
  8. Ann-Katrin Nilsson
  9. Linda Karlsson
  10. Nicholas Gaiano
  11. Keejung Yoon
  12. Janet Rossant
  13. M. Luisa Iruela-Arispe
  14. Mattias Kalén
  15. Holger Gerhardt
  16. Christer Betsholtz
Corresponding authors

Correspondence to Mats Hellström or Holger Gerhardt.

Ethics declarations Competing interests

[Competing Interests Statement: M.H. and M.K. are employed by AngioGenetics Sweden AB. C.B. receives funding from and is a consultant of AngioGenetics Sweden AB.]

Supplementary information Supplementary Information

This file contains Supplementary Methods, Supplementary Figures S1-S11 with Legends and additional references. (PDF 7910 kb)

About this article Cite this article

Hellström, M., Phng, LK., Hofmann, J. et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776–780 (2007). https://doi.org/10.1038/nature05571

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