Castillo, SD;
Tzouanacou, E;
Zaw-Thin, M;
Berenjeno, IM;
Parker, VE;
Chivite, I;
Milà-Guasch, M;
... Vanhaesebroeck, B; + view all
(2016)
Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.
Science Translational Medicine
, 8
(332)
, Article 332ra43. 10.1126/scitranslmed.aad9982.
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Castillo et al Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans Supplementary info.pdf Download (624kB) | Preview |
Abstract
Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in theTEKgene, 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 ofPik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression ofPik3ca(H1047R)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 activatingPIK3CAmutations in human VMs, mutually exclusive withTEKmutations. Our data demonstrate a causal relationship between activatingPik3camutations 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.
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