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

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          Abstract

          <p class="first" id="P3">Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, present from birth. Mutations in the <i>TEK</i> gene, encoding the tyrosine kinase receptor TIE2, are found in approximately half of sporadic (non-familial) 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. In this study, we have generated a mouse model that faithfully mirrors human VM through mosaic expression of <i>Pik3ca <sup>H1047R</sup> </i>, a constitutively active mutant of the p110α isoform of PI 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of <i>Pik3ca <sup>H1047R</sup> </i> 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 endothelial cell hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression <i>in vivo</i>. In line with the mouse data, we also report the presence of activating <i>PIK3CA</i> mutations in human VMs, mutually exclusive with <i>TEK</i> mutations. Our data demonstrate a causal relationship between activating <i>Pik3ca</i> 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. </p>

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          Author and article information

          Journal
          Science Translational Medicine
          Science Translational Medicine
          American Association for the Advancement of Science (AAAS)
          1946-6234
          1946-6242
          March 30 2016
          March 30 2016
          : 8
          : 332
          : 332ra43
          Article
          10.1126/scitranslmed.aad9982
          5973268
          27030595
          bd97e949-a639-44a5-bbe5-2af31bb3f4e4
          © 2016
          History

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