Negative Regulators of Vessel Patterning

  1. Derek J. Chadwick Organizer and
  2. Jamie Goode
  1. Steven Suchting1,
  2. Catarina Freitas1,
  3. Ferdinand le Noble1,
  4. Rui Benedito2,
  5. Christiane Bréant1,
  6. Antonio Duarte2 and
  7. Anne Eichmann1

Published Online: 11 SEP 2007

DOI: 10.1002/9780470319413.ch7

Vascular Development: Novartis Foundation Symposium 283

Vascular Development: Novartis Foundation Symposium 283

How to Cite

Suchting, S., Freitas, C., le Noble, F., Benedito, R., Bréant, C., Duarte, A. and Eichmann, A. (2007) Negative Regulators of Vessel Patterning, in Vascular Development: Novartis Foundation Symposium 283 (eds D. J. Chadwick and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/9780470319413.ch7

Author Information

  1. 1

    Institut National de la Santé et de la Recherche Medicale U833, Collège de France, 11 Place Marcelin Berthelot, 75005 Paris, France

  2. 2

    Technical University of Lisbon, Portugal

Publication History

  1. Published Online: 11 SEP 2007
  2. Published Print: 20 JUL 2007

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470034286

Online ISBN: 9780470319413



  • vessel patterning negative regulators;
  • Notch ligand Delta-like 4 (Dll4);
  • normal angiogenic sprouting and VEGF;
  • Dll4 - vascular sprouting novel negative regulator;
  • Notch signalling


Blood vessels and nerves are structurally similar, complex branched networks that require guidance to ensure their proper positioning in the body. Recent studies have demonstrated that specialized endothelial cells, resembling axonal growth cones, are located at the tips of growing capillaries. These endothelial tip cells guide outgrowing capillaries in response to gradients of extracellular matrix-bound vascular endothelial growth factor (VEGF). Here we show that endothelial tip cell formation and vessel branching are negatively regulated by the Notch ligand Delta-like 4 (Dll4). Heterozygous deletion of Dll4 or pharmacological inhibition of Notch signalling using γ-secretase inhibitor revealed a striking vascular phenotype, with greatly increased numbers of filopodia-extending endothelial tip cells and increased expression of tip cell marker genes compared to controls. Filopodia extension in Dll4+/− retinal vessels required VEGF and was inhibited when VEGF signalling was blocked. While VEGF expression was not significantly altered in Dll4+/− retinas, Dll4+/− vessels showed increased expression of VEGF Receptor 2 and decreased expression of VEGF Receptor 1 compared to wildtype, suggesting that they could be more responsive to VEGF stimulation. In addition, expression of Dll4 in wildtype tip cells was itself decreased when VEGF signalling was blocked, indicating that Dll4 may act downstream of VEGF as a ‘brake’ on VEGF-mediated angiogenic sprouting. Taken together, these data reveal Dll4 as a novel negative regulator of vascular sprouting and vessel branching that is required for normal vascular network formation during development.