PUBLICATION

Positive Feedback Defines the Timing, Magnitude, and Robustness of Angiogenesis

Authors
Page, D.J., Thuret, R., Venkatraman, L., Takahashi, T., Bentley, K., Herbert, S.P.
ID
ZDB-PUB-190613-12
Date
2019
Source
Cell Reports   27: 3139-3151.e5 (Journal)
Registered Authors
Herbert, Shane, Takahashi, Tokiharu, Thuret, Raphael
Keywords
angiogenesis, endothelial cell, lateral inhibition, positive feedback, tetraspanin, tip cell
MeSH Terms
  • Animals
  • Humans
  • Tetraspanins/genetics
  • Tetraspanins/metabolism
  • Neovascularization, Physiologic*
  • Vascular Endothelial Growth Factor A/metabolism
  • Feedback, Physiological*
  • Zebrafish
  • Receptors, Notch/metabolism
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Human Umbilical Vein Endothelial Cells/physiology
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
(all 13)
PubMed
31189101 Full text @ Cell Rep.
Abstract
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 positive-feedback-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 spatiotemporally shapes the angiogenic switch to ultimately modulate vascular network topology.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
s5
    Point Mutation
    s843TgTransgenic Insertion
      ubs1TgTransgenic Insertion
        umc201
          Indel
          umc202
            Small Deletion
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            dll4MO1-dll4MRPHLNO
            flt1MO3-flt1MRPHLNO
            tm4sf18CRISPR1-tm4sf18CRISPR
            tm4sf18TALEN1-tm4sf18TALEN
            1 - 4 of 4
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            Fish
            Antibodies
            Name Type Antigen Genes Isotypes Host Organism
            Ab9-mapkmonoclonal
              IgGRabbit
              Ab11-mapkmonoclonal
                IgGRabbit
                Ab20-mapkmonoclonal
                  IgGRabbit
                  1 - 3 of 3
                  Show
                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  EGFPEFGEGFP
                  1 - 1 of 1
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                  Mapping
                  No data available