title: Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.
abstract: 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 Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(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 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.
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Castillo
authors.affiliation: MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK. Institut Pasteur, Département de Biologie du Développement, CNRS URA 2578, 75724 Paris cedex 15, France.
authors.forename: Elena
authors.initials: E
authors.lastname: Tzouanacou
authors.affiliation: Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.
authors.forename: May
authors.initials: M
authors.lastname: Zaw-Thin
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Inma M
authors.initials: IM
authors.lastname: Berenjeno
authors.affiliation: Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Victoria E R
authors.initials: VE
authors.lastname: Parker
authors.affiliation: Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Chivite
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Milà-Guasch
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Wayne
authors.initials: W
authors.lastname: Pearce
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Solomon
authors.affiliation: Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Angulo-Urarte
authors.affiliation: Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Figueiredo
authors.affiliation: MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Dewhurst
authors.affiliation: Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Knox
authors.affiliation: Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Clark
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell OX11 0RD, UK.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Scudamore
authors.affiliation: Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Badar
authors.affiliation: Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Kalber
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Foster
authors.affiliation: Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Stuckey
authors.affiliation: UCL Institute for Women's Health, London WC1E 6BT, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: David
authors.affiliation: Cancer Biology and Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia. Department of Surgery (St. Vincent's Hospital), University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.affiliation: Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.affiliation: MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Wilson
authors.affiliation: Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.affiliation: UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.affiliation: UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Kinsler
authors.affiliation: Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008648:Mesoderm / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D008810:Mice, Inbred C57BL; D009030:Mosaicism / Q000187:drug effects; D009154:Mutation / Q000235:genetics*; D020286:Pericytes / Q000187:drug effects / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D042787:Receptor, TIE-2 / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D054079:Vascular Malformations / Q000201:enzymology* / Q000235:genetics*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C546639:Pik3ca protein, mouse; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D020123:Sirolimus