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In Vitro Three-Dimensional Sprouting Assay of Angiogenesis Using Mouse Embryonic Stem Cells for Vascular Disease Modeling and Drug Testing
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Agent-based simulation of notch-mediated tip cell selection in angiogenic sprout initialisation.

Katie Bentley1, Holger Gerhardt, Paul A Bates

  • 1Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK. katie.bentley@cancer.org.uk <katie.bentley@cancer.org.uk>

Journal of Theoretical Biology
|November 22, 2007
PubMed
Summary

A new model explains how cells become tip or stalk cells during blood vessel growth. It highlights vascular endothelial growth factor-A (VEGF-A) and delta-like 4 (Dll4)/notch signaling as key to this process.

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Area of Science:

  • * Developmental Biology
  • * Computational Biology
  • * Cell Biology

Background:

  • * Angiogenic sprouting involves endothelial cell specialization into tip and stalk cells.
  • * Vascular endothelial growth factor-A (VEGF-A) induces tip cell phenotype, but tip cell selection mechanisms remain unclear.
  • * Understanding tip/stalk cell patterning is crucial for addressing vascular diseases.

Purpose of the Study:

  • * To simulate the feedback loop linking VEGF-A-induced tip cell phenotype with delta-like 4 (Dll4)/notch-mediated lateral inhibition.
  • * To identify critical parameters influencing tip/stalk cell patterning robustness.
  • * To provide mechanistic insights into vascular patterning defects in diseases with high VEGF-A.

Main Methods:

  • * Development of a hierarchical agent-based model.
  • * Simulation of VEGF-A concentration, VEGF-A gradients, and filopodia extension.
  • * Investigation of cell morphology's role in tip/stalk patterning.

Main Results:

  • * VEGF-A concentration, gradients, and filopodia extension are critical for tip/stalk patterning.
  • * Filopodia act as lateral inhibition amplifiers.
  • * Model predicts oscillations in Dll4/VEGFR-2 levels in high VEGF environments and increased tip cell selection with VEGF gradients.

Conclusions:

  • * The model offers new mechanistic insights into vascular patterning.
  • * It explains defects observed in pathological angiogenesis (e.g., diabetic retinopathy, tumor angiogenesis).
  • * Filopodia play a significant role in amplifying lateral inhibition for cell specialization.