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Related Experiment Video

Updated: Jun 29, 2025

In Vitro Three-Dimensional Sprouting Assay of Angiogenesis Using Mouse Embryonic Stem Cells for Vascular Disease Modeling and Drug Testing
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A brain-specific angiogenic mechanism enabled by tip cell specialization.

Giel Schevenels1, Pauline Cabochette1, Michelle America1

  • 1Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles (ULB), Gosselies, Belgium.

Nature
|April 3, 2024
PubMed
Summary

Brain blood vessel development relies on Wnt7a/b signaling controlling Mmp25 expression. This mechanism guides endothelial tip cell migration across the brain

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Vascular Biology

Background:

  • Vertebrate organs possess unique blood vessels tailored to their specific functions.
  • The development of these organ-specific vessels is often considered independent of the general vascularization process.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying brain-specific blood vessel formation (angiogenesis).
  • To challenge the notion that organotypic vessel specialization is unrelated to vascularization processes.

Main Methods:

  • Utilized CRISPR-Cas9 mutagenesis in zebrafish to study gene function.
  • Investigated the role of Wnt7a/b ligands and Mmp25 in brain angiogenesis.
  • Analyzed the cleavage of collagen IV chains by Mmp25.
  • Examined the impact of genetic interference with the pial basement membrane.

Main Results:

  • Identified a Wnt7a/b-dependent pathway controlling brain angiogenesis via Mmp25 expression in endothelial cells.
  • Demonstrated Mmp25's crucial role in endothelial tip cell migration across the pial basement membrane.
  • Showed Mmp25 cleaves specific collagen IV chains, facilitating brain invasion.
  • Found that disrupting the pial basement membrane impairs Wnt-β-catenin-dependent angiogenesis, leading to defective blood-brain barriers.

Conclusions:

  • Revealed a novel mechanism for organ-specific angiogenesis controlled by local cues (Wnt7a/b) and specific proteases (Mmp25).
  • Highlighted the importance of endothelial tip cell interactions with the extracellular matrix for brain vascularization.
  • Established a link between organotypic control, angiogenesis, and blood-brain barrier integrity.