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

Sandra D. Castillo*, Elena Tzouanacou, May Zaw-Thin, Inma M. Berenjeno, Victoria E.R. Parker, Iñigo Chivite, Maria Milà-Guasch, Wayne Pearce, Isabelle Solomon, Ana Angulo-Urarte, Ana M. Figueiredo, Robert E. Dewhurst, Rachel G. Knox, Graeme R. Clark, Cheryl L. Scudamore, Adam Badar, Tammy L. Kalber, Julie Foster, Daniel J. Stuckey, Anna L. DavidWayne A. Phillips, Mark F. Lythgoe, Valerie Wilson, Robert K. Semple, Neil J. Sebire, Veronica A. Kinsler, Mariona Graupera, Bart Vanhaesebroeck

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3caH1047R, a constitutively active mutant of the p110a isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3caH1047R resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs.

Original languageEnglish
Article number332ra43
JournalScience Translational Medicine
Issue number332
StatePublished - 30 Mar 2016
Externally publishedYes


Dive into the research topics of 'Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans'. Together they form a unique fingerprint.

Cite this