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Related Experiment Videos

Negative regulators of vessel patterning.

Steven Suchting1, Catarina Freitas, Ferdinand le Noble

  • 1Inserm U833, Collge de France, 11 Place Marcelin Berthelot, 75005 Paris, France.

Novartis Foundation Symposium
|February 28, 2008
PubMed
Summary
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Delta-like 4 (Dll4) negatively regulates blood vessel formation. Inhibiting Dll4 increases endothelial tip cells and vessel branching, suggesting Dll4 acts as a brake on vascular sprouting.

Area of Science:

  • Developmental Biology
  • Cell Biology
  • Vascular Biology

Background:

  • Blood vessels and nerves share structural similarities as complex branched networks.
  • Specialized endothelial tip cells, analogous to axonal growth cones, guide capillary growth.
  • Vascular endothelial growth factor (VEGF) gradients guide capillary sprouting.

Purpose of the Study:

  • To investigate the role of the Notch ligand Delta-like 4 (Dll4) in regulating endothelial tip cell formation and vascular branching.
  • To elucidate the relationship between Dll4, VEGF signaling, and angiogenic sprouting.

Main Methods:

  • Analysis of vascular phenotypes in heterozygous Dll4-deleted (Dll4+/-) mice.
  • Pharmacological inhibition of Notch signaling using a gamma-secretase inhibitor.

Related Experiment Videos

  • Assessment of endothelial tip cell markers, filopodia extension, and receptor expression (VEGF Receptor 1 and 2).

    • Main Results:

    • Dll4 heterozygous deletion or Notch inhibition led to increased endothelial tip cells and vessel branching.
    • Filopodia extension in Dll4+/- retinal vessels was dependent on VEGF signaling.
    • Dll4+/- vessels exhibited altered VEGF receptor expression, suggesting enhanced VEGF responsiveness.
    • Dll4 expression in tip cells decreased upon VEGF signaling blockade, indicating Dll4 acts downstream of VEGF.

    Conclusions:

    • Dll4 functions as a novel negative regulator of vascular sprouting and branching.
    • Dll4 is essential for normal vascular network formation during development.
    • Dll4 acts as a 'brake' on VEGF-mediated angiogenic sprouting, balancing vessel growth.