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

Sandra Castillo, Elena Tzouanacou, May Zaw-Thin, Inma Berenjeno, Victoria parker, Inigo Chivite, Maria Mila-Guasch, Wayne Pearce, Isabelle Solomon, Anna Angulo-Urarte, Ana Figueiredo, Robert Dewhurst, Rachel Knox, Graeme Clark, Cheryl Scudamore, Adam Badar, Tammy Kalber, Julie Foster, Daniel Stuckey, Anna DavidWayne Phillips, Mark Lythgoe, Valerie Wilson, Robert Semple, Neil Seribe, Veronica Kinsler, Mariona Graupera, Bart Vanhaesebroeck

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated veins, present from birth. Mutations in the tyrosine kinase receptor TIE2 have been found in approximately half of sporadic (non-familial) VMs, with the cause of the other cases unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient and targeted therapy for this disease remains underexplored. By mosaic expression in the embryonic mesoderm of Pik3caH1047R, a constitutively active mutant of the p110α isoform of PI 3-kinase (PI3K), we have generated a genetically-engineered mouse model with vascular lesions present in newborn pups, which faithfully mirrors human VMs. In line with this, we (and Castel et al., in the accompanying paper) have found activating PIK3CA mutations in human VMs, mutually exclusive with TIE2 mutations. Endothelial cell (EC)-specific expression of Pik3caH1047R in newborn mice resulted in EC hyperproliferation and impaired pericyte coverage, both of which could be normalized by PI3K pathway inhibition by rapamycin. Moreover, in vivo rapamycin therapy led to regression of mesodermally-induced Pik3caH1047R VMs. Our data demonstrate a causal relationship between activating Pik3ca mutation and the genesis of VMs, provide the first genetic model that faithfully mirrors the normal etiology and development of this human disease and establish proof-of-principle for the use of PI3K-targeted therapies in VMs.
Original languageEnglish
Article number332ra43
JournalScience Translational Medicine
Issue number332
Publication statusPublished - 30 Mar 2016


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