Somatic PIK3CA mutations as a driver of sporadic venous malformations

Sci Transl Med. 2016 Mar 30;8(332):332ra42. doi: 10.1126/scitranslmed.aaf1164.


Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyenet al, 2014; Uebelhoeret al, 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limayeet al, 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Class I Phosphatidylinositol 3-Kinases
  • Embryo, Mammalian / blood supply
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / pathology
  • Endothelial Cells / metabolism
  • Integrases / metabolism
  • Mice
  • Mutation / genetics*
  • Neovascularization, Physiologic / drug effects
  • Phosphatidylinositol 3-Kinases / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Skin / blood supply
  • Skin / pathology
  • Spinal Cord / blood supply
  • Spinal Cord / pathology
  • Vascular Malformations / drug therapy
  • Vascular Malformations / enzymology*
  • Vascular Malformations / genetics*


  • Protein Kinase Inhibitors
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Pik3ca protein, mouse
  • Cre recombinase
  • Integrases