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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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Control of endothelial sprouting by a Tel-CtBP complex.

M Guy Roukens1, Mariam Alloul-Ramdhani, Bart Baan

  • 1Leiden University Medical Center (LUMC), Section of Growth Control and Transcription, Department of Molecular Cell Biology, 2300 RC Leiden, The Netherlands.

Nature Cell Biology
|September 14, 2010
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Summary

The transcriptional repressor Tel is essential for blood vessel formation (angiogenesis) in humans and zebrafish. It balances growth and inhibitory signals, offering potential therapeutic targets for diseases involving abnormal blood vessel growth.

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Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Background:

  • Angiogenesis, the formation of new blood vessels, is crucial for development and tissue repair.
  • Dysregulated angiogenesis is implicated in various diseases, including cancer and diabetic retinopathy.
  • Understanding the molecular mechanisms controlling angiogenesis is vital for therapeutic interventions.

Purpose of the Study:

  • To investigate the role of the transcriptional repressor Tel in angiogenesis.
  • To elucidate the molecular mechanisms by which Tel regulates endothelial cell behavior during blood vessel formation.
  • To identify potential therapeutic targets for inhibiting pathological angiogenesis.

Main Methods:

  • Studied the function of Tel in human endothelial cells and in the model organism Danio rerio (zebrafish).
  • Investigated the interaction of Tel with the co-repressor CtBP.
  • Analyzed the regulation of key signaling pathways, including VEGF, Dll4, and Notch, by the Tel-CtBP complex.
  • Examined the role of Tel in controlling the expression of genes involved in angiogenesis, such as sprouty family members and ve-cadherin.

Main Results:

  • Tel is indispensable for endothelial cell sprouting and the development of the zebrafish circulatory system.
  • The Tel-CtBP complex restricts VEGF-mediated Dll4 expression, linking intracellular VEGF signaling to intercellular Notch-Dll4 signaling.
  • Tel regulates branching by controlling factors that constrain angiogenesis, such as sprouty proteins and ve-cadherin.
  • Tel's role in branching is an evolutionarily refined mechanism from invertebrate tracheal development.

Conclusions:

  • The Tel-CtBP complex is a key regulator of angiogenesis, balancing pro-angiogenic and anti-angiogenic cues.
  • Tel acts as a crucial link between growth factor signaling and cell-cell communication in endothelial cells.
  • Tel and its associated regulatory networks represent promising targets for therapeutic strategies aimed at inhibiting pathological angiogenesis.