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Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans

Sandra D Castillo1, Elena Tzouanacou2, May Zaw-Thin3

  • 1UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.

Science Translational Medicine
|April 1, 2016
PubMed

Insights

Activating mutations in PIK3CA cause venous malformations (VMs), painful vascular lesions. Targeting the PI3K pathway with rapamycin offers a potential new therapy for these common, deforming birth defects.

Area of Science:

  • Vascular biology
  • Genetics
  • Developmental biology

Background:

  • Venous malformations (VMs) are congenital vascular lesions causing pain and disfigurement.
  • TEK gene mutations explain about half of sporadic VMs; other causes are unknown.
  • Current treatments like sclerotherapy have limited efficacy, and targeted therapies are underexplored.

Purpose of the Study:

  • To investigate the genetic basis of VMs beyond TEK mutations.
  • To develop a faithful mouse model for studying VM pathogenesis.
  • To explore PI3K pathway inhibition as a therapeutic strategy for VMs.

Main Methods:

  • Generated a mouse model with mosaic expression of a constitutively active PIK3CA mutation (Pik3ca(H1047R)) in the embryonic mesoderm.
  • Analyzed endothelial cell proliferation, pericyte coverage, and arteriovenous specification markers.
  • Administered PI3K pathway inhibitor (rapamycin) to assess therapeutic effects in vivo.
  • Sequenced human VM samples to identify PIK3CA mutations.

Main Results:

  • Mosaic Pik3ca(H1047R) expression in mice led to VM-like phenotypes: endothelial cell hyperproliferation, reduced pericyte coverage, and altered arteriovenous markers.
  • Rapamycin treatment normalized vascular defects and induced VM regression in the mouse model.
  • Activating PIK3CA mutations were identified in human VMs, mutually exclusive with TEK mutations.

Conclusions:

  • Activating PIK3CA mutations are a key cause of venous malformations.
  • The developed mouse model accurately reflects human VM etiology and development.
  • PI3K pathway inhibition represents a promising therapeutic avenue for treating venous malformations.

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