Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.
Identifieur interne : 001729 ( Main/Curation ); précédent : 001728; suivant : 001730Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.
Auteurs : Sandra D. Castillo [Royaume-Uni] ; Elena Tzouanacou [France] ; May Zaw-Thin [Royaume-Uni] ; Inma M. Berenjeno [Royaume-Uni] ; Victoria E R. Parker [Royaume-Uni] ; I Igo Chivite [Espagne] ; Maria Milà-Guasch [Royaume-Uni] ; Wayne Pearce [Royaume-Uni] ; Isabelle Solomon [Royaume-Uni] ; Ana Angulo-Urarte [Espagne] ; Ana M. Figueiredo [Espagne] ; Robert E. Dewhurst [Royaume-Uni] ; Rachel G. Knox [Royaume-Uni] ; Graeme R. Clark [Royaume-Uni] ; Cheryl L. Scudamore [Royaume-Uni] ; Adam Badar [Royaume-Uni] ; Tammy L. Kalber [Royaume-Uni] ; Julie Foster [Royaume-Uni] ; Daniel J. Stuckey [Royaume-Uni] ; Anna L. David [Royaume-Uni] ; Wayne A. Phillips [Australie] ; Mark F. Lythgoe [Royaume-Uni] ; Valerie Wilson [Royaume-Uni] ; Robert K. Semple [Royaume-Uni] ; Neil J. Sebire [Royaume-Uni] ; Veronica A. Kinsler [Royaume-Uni] ; Mariona Graupera [Espagne] ; Bart Vanhaesebroeck [Royaume-Uni]Source :
- Science translational medicine [ 1946-6242 ] ; 2016.
Descripteurs français
- KwdFr :
- Animaux, Anomalies vasculaires (enzymologie), Anomalies vasculaires (génétique), Cellules endothéliales (), Cellules endothéliales (anatomopathologie), Humains, Mosaïcisme (), Mutation (génétique), Mésoderme (), Mésoderme (anatomopathologie), Mésoderme (embryologie), Phosphatidylinositol 3-kinases (génétique), Prolifération cellulaire (), Péricytes (), Péricytes (anatomopathologie), Récepteur TIE-2 (métabolisme), Sirolimus (pharmacologie), Souris de lignée C57BL.
- MESH :
- anatomopathologie : Cellules endothéliales, Mésoderme, Péricytes.
- embryologie : Mésoderme.
- enzymologie : Anomalies vasculaires.
- génétique : Anomalies vasculaires, Mutation, Phosphatidylinositol 3-kinases.
- métabolisme : Récepteur TIE-2.
- pharmacologie : Sirolimus.
- Animaux, Cellules endothéliales, Humains, Mosaïcisme, Mésoderme, Prolifération cellulaire, Péricytes, Souris de lignée C57BL.
English descriptors
- KwdEn :
- Animals, Cell Proliferation (drug effects), Endothelial Cells (drug effects), Endothelial Cells (pathology), Humans, Mesoderm (drug effects), Mesoderm (embryology), Mesoderm (pathology), Mice, Inbred C57BL, Mosaicism (drug effects), Mutation (genetics), Pericytes (drug effects), Pericytes (pathology), Phosphatidylinositol 3-Kinases (genetics), Receptor, TIE-2 (metabolism), Sirolimus (pharmacology), Vascular Malformations (enzymology), Vascular Malformations (genetics).
- MESH :
- chemical , genetics : Phosphatidylinositol 3-Kinases.
- drug effects : Cell Proliferation, Endothelial Cells, Mesoderm, Mosaicism, Pericytes.
- embryology : Mesoderm.
- enzymology : Vascular Malformations.
- genetics : Mutation, Vascular Malformations.
- chemical , metabolism : Receptor, TIE-2.
- pathology : Endothelial Cells, Mesoderm, Pericytes.
- chemical , pharmacology : Sirolimus.
- Animals, Humans, Mice, Inbred C57BL.
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.
DOI: 10.1126/scitranslmed.aad9982
PubMed: 27030595
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pubmed:27030595Le document en format XML
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Castillo</name><affiliation wicri:level="4"><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Cancer Institute, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Tzouanacou, Elena" sort="Tzouanacou, Elena" uniqKey="Tzouanacou E" first="Elena" last="Tzouanacou">Elena Tzouanacou</name><affiliation wicri:level="4"><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK. 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Figueiredo</name><affiliation wicri:level="1"><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Dewhurst, Robert E" sort="Dewhurst, Robert E" uniqKey="Dewhurst R" first="Robert E" last="Dewhurst">Robert E. Dewhurst</name><affiliation wicri:level="4"><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU</wicri:regionArea><orgName type="university">Université d'Édimbourg</orgName><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Knox, Rachel G" sort="Knox, Rachel G" uniqKey="Knox R" first="Rachel G" last="Knox">Rachel G. Knox</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Clark, Graeme R" sort="Clark, Graeme R" uniqKey="Clark G" first="Graeme R" last="Clark">Graeme R. Clark</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Scudamore, Cheryl L" sort="Scudamore, Cheryl L" uniqKey="Scudamore C" first="Cheryl L" last="Scudamore">Cheryl L. Scudamore</name><affiliation wicri:level="1"><nlm:affiliation>Mary Lyon Centre, MRC Harwell, Harwell OX11 0RD, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Mary Lyon Centre, MRC Harwell, Harwell OX11 0RD</wicri:regionArea><wicri:noRegion>Harwell OX11 0RD</wicri:noRegion></affiliation></author><author><name sortKey="Badar, Adam" sort="Badar, Adam" uniqKey="Badar A" first="Adam" last="Badar">Adam Badar</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Kalber, Tammy L" sort="Kalber, Tammy L" uniqKey="Kalber T" first="Tammy L" last="Kalber">Tammy L. Kalber</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Foster, Julie" sort="Foster, Julie" uniqKey="Foster J" first="Julie" last="Foster">Julie Foster</name><affiliation wicri:level="4"><nlm:affiliation>Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ</wicri:regionArea><orgName type="university">Université de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Stuckey, Daniel J" sort="Stuckey, Daniel J" uniqKey="Stuckey D" first="Daniel J" last="Stuckey">Daniel J. Stuckey</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="David, Anna L" sort="David, Anna L" uniqKey="David A" first="Anna L" last="David">Anna L. David</name><affiliation wicri:level="1"><nlm:affiliation>UCL Institute for Women's Health, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute for Women's Health, London WC1E 6BT</wicri:regionArea><wicri:noRegion>London WC1E 6BT</wicri:noRegion></affiliation></author><author><name sortKey="Phillips, Wayne A" sort="Phillips, Wayne A" uniqKey="Phillips W" first="Wayne A" last="Phillips">Wayne A. Phillips</name><affiliation wicri:level="4"><nlm: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.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>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</wicri:regionArea><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Lythgoe, Mark F" sort="Lythgoe, Mark F" uniqKey="Lythgoe M" first="Mark F" last="Lythgoe">Mark F. Lythgoe</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Wilson, Valerie" sort="Wilson, Valerie" uniqKey="Wilson V" first="Valerie" last="Wilson">Valerie Wilson</name><affiliation wicri:level="4"><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU</wicri:regionArea><orgName type="university">Université d'Édimbourg</orgName><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Semple, Robert K" sort="Semple, Robert K" uniqKey="Semple R" first="Robert K" last="Semple">Robert K. Semple</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Sebire, Neil J" sort="Sebire, Neil J" uniqKey="Sebire N" first="Neil J" last="Sebire">Neil J. Sebire</name><affiliation wicri:level="1"><nlm:affiliation>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH</wicri:regionArea><wicri:noRegion>London WC1N 3JH</wicri:noRegion></affiliation></author><author><name sortKey="Kinsler, Veronica A" sort="Kinsler, Veronica A" uniqKey="Kinsler V" first="Veronica A" last="Kinsler">Veronica A. Kinsler</name><affiliation wicri:level="1"><nlm:affiliation>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH</wicri:regionArea><wicri:noRegion>London WC1N 3JH</wicri:noRegion></affiliation></author><author><name sortKey="Graupera, Mariona" sort="Graupera, Mariona" uniqKey="Graupera M" first="Mariona" last="Graupera">Mariona Graupera</name><affiliation wicri:level="1"><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Vanhaesebroeck, Bart" sort="Vanhaesebroeck, Bart" uniqKey="Vanhaesebroeck B" first="Bart" last="Vanhaesebroeck">Bart Vanhaesebroeck</name><affiliation wicri:level="4"><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Cancer Institute, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27030595</idno><idno type="pmid">27030595</idno><idno type="doi">10.1126/scitranslmed.aad9982</idno><idno type="wicri:Area/PubMed/Corpus">002173</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002173</idno><idno type="wicri:Area/PubMed/Curation">002147</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002147</idno><idno type="wicri:Area/PubMed/Checkpoint">002147</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">002147</idno><idno type="wicri:Area/Ncbi/Merge">003346</idno><idno type="wicri:Area/Ncbi/Curation">003346</idno><idno type="wicri:Area/Ncbi/Checkpoint">003346</idno><idno type="wicri:Area/Main/Merge">001724</idno><idno type="wicri:Area/Main/Curation">001729</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.</title><author><name sortKey="Castillo, Sandra D" sort="Castillo, Sandra D" uniqKey="Castillo S" first="Sandra D" last="Castillo">Sandra D. Castillo</name><affiliation wicri:level="4"><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Cancer Institute, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Tzouanacou, Elena" sort="Tzouanacou, Elena" uniqKey="Tzouanacou E" first="Elena" last="Tzouanacou">Elena Tzouanacou</name><affiliation wicri:level="4"><nlm: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.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>75724 Paris cedex 15</wicri:noRegion><orgName type="university">Université d'Édimbourg</orgName><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Zaw Thin, May" sort="Zaw Thin, May" uniqKey="Zaw Thin M" first="May" last="Zaw-Thin">May Zaw-Thin</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Berenjeno, Inma M" sort="Berenjeno, Inma M" uniqKey="Berenjeno I" first="Inma M" last="Berenjeno">Inma M. Berenjeno</name><affiliation wicri:level="4"><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Cancer Institute, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Parker, Victoria E R" sort="Parker, Victoria E R" uniqKey="Parker V" first="Victoria E R" last="Parker">Victoria E R. Parker</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Chivite, I Igo" sort="Chivite, I Igo" uniqKey="Chivite I" first="I Igo" last="Chivite">I Igo Chivite</name><affiliation wicri:level="1"><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Mila Guasch, Maria" sort="Mila Guasch, Maria" uniqKey="Mila Guasch M" first="Maria" last="Milà-Guasch">Maria Milà-Guasch</name><affiliation wicri:level="4"><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Cancer Institute, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Pearce, Wayne" sort="Pearce, Wayne" uniqKey="Pearce W" first="Wayne" last="Pearce">Wayne Pearce</name><affiliation wicri:level="4"><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Cancer Institute, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Solomon, Isabelle" sort="Solomon, Isabelle" uniqKey="Solomon I" first="Isabelle" last="Solomon">Isabelle Solomon</name><affiliation wicri:level="4"><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Cancer Institute, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Angulo Urarte, Ana" sort="Angulo Urarte, Ana" uniqKey="Angulo Urarte A" first="Ana" last="Angulo-Urarte">Ana Angulo-Urarte</name><affiliation wicri:level="1"><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Figueiredo, Ana M" sort="Figueiredo, Ana M" uniqKey="Figueiredo A" first="Ana M" last="Figueiredo">Ana M. Figueiredo</name><affiliation wicri:level="1"><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Dewhurst, Robert E" sort="Dewhurst, Robert E" uniqKey="Dewhurst R" first="Robert E" last="Dewhurst">Robert E. Dewhurst</name><affiliation wicri:level="4"><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU</wicri:regionArea><orgName type="university">Université d'Édimbourg</orgName><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Knox, Rachel G" sort="Knox, Rachel G" uniqKey="Knox R" first="Rachel G" last="Knox">Rachel G. Knox</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Clark, Graeme R" sort="Clark, Graeme R" uniqKey="Clark G" first="Graeme R" last="Clark">Graeme R. Clark</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Scudamore, Cheryl L" sort="Scudamore, Cheryl L" uniqKey="Scudamore C" first="Cheryl L" last="Scudamore">Cheryl L. Scudamore</name><affiliation wicri:level="1"><nlm:affiliation>Mary Lyon Centre, MRC Harwell, Harwell OX11 0RD, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Mary Lyon Centre, MRC Harwell, Harwell OX11 0RD</wicri:regionArea><wicri:noRegion>Harwell OX11 0RD</wicri:noRegion></affiliation></author><author><name sortKey="Badar, Adam" sort="Badar, Adam" uniqKey="Badar A" first="Adam" last="Badar">Adam Badar</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Kalber, Tammy L" sort="Kalber, Tammy L" uniqKey="Kalber T" first="Tammy L" last="Kalber">Tammy L. Kalber</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Foster, Julie" sort="Foster, Julie" uniqKey="Foster J" first="Julie" last="Foster">Julie Foster</name><affiliation wicri:level="4"><nlm:affiliation>Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ</wicri:regionArea><orgName type="university">Université de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Stuckey, Daniel J" sort="Stuckey, Daniel J" uniqKey="Stuckey D" first="Daniel J" last="Stuckey">Daniel J. Stuckey</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="David, Anna L" sort="David, Anna L" uniqKey="David A" first="Anna L" last="David">Anna L. David</name><affiliation wicri:level="1"><nlm:affiliation>UCL Institute for Women's Health, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute for Women's Health, London WC1E 6BT</wicri:regionArea><wicri:noRegion>London WC1E 6BT</wicri:noRegion></affiliation></author><author><name sortKey="Phillips, Wayne A" sort="Phillips, Wayne A" uniqKey="Phillips W" first="Wayne A" last="Phillips">Wayne A. Phillips</name><affiliation wicri:level="4"><nlm: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.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>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</wicri:regionArea><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Lythgoe, Mark F" sort="Lythgoe, Mark F" uniqKey="Lythgoe M" first="Mark F" last="Lythgoe">Mark F. Lythgoe</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Wilson, Valerie" sort="Wilson, Valerie" uniqKey="Wilson V" first="Valerie" last="Wilson">Valerie Wilson</name><affiliation wicri:level="4"><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU</wicri:regionArea><orgName type="university">Université d'Édimbourg</orgName><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Semple, Robert K" sort="Semple, Robert K" uniqKey="Semple R" first="Robert K" last="Semple">Robert K. Semple</name><affiliation wicri:level="4"><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Sebire, Neil J" sort="Sebire, Neil J" uniqKey="Sebire N" first="Neil J" last="Sebire">Neil J. Sebire</name><affiliation wicri:level="1"><nlm:affiliation>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH</wicri:regionArea><wicri:noRegion>London WC1N 3JH</wicri:noRegion></affiliation></author><author><name sortKey="Kinsler, Veronica A" sort="Kinsler, Veronica A" uniqKey="Kinsler V" first="Veronica A" last="Kinsler">Veronica A. Kinsler</name><affiliation wicri:level="1"><nlm:affiliation>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH</wicri:regionArea><wicri:noRegion>London WC1N 3JH</wicri:noRegion></affiliation></author><author><name sortKey="Graupera, Mariona" sort="Graupera, Mariona" uniqKey="Graupera M" first="Mariona" last="Graupera">Mariona Graupera</name><affiliation wicri:level="1"><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Vanhaesebroeck, Bart" sort="Vanhaesebroeck, Bart" uniqKey="Vanhaesebroeck B" first="Bart" last="Vanhaesebroeck">Bart Vanhaesebroeck</name><affiliation wicri:level="4"><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Cancer Institute, University College London, London WC1E 6BT</wicri:regionArea><orgName type="university">University College de Londres</orgName><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author></analytic><series><title level="j">Science translational medicine</title><idno type="eISSN">1946-6242</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Cell Proliferation (drug effects)</term><term>Endothelial Cells (drug effects)</term><term>Endothelial Cells (pathology)</term><term>Humans</term><term>Mesoderm (drug effects)</term><term>Mesoderm (embryology)</term><term>Mesoderm (pathology)</term><term>Mice, Inbred C57BL</term><term>Mosaicism (drug effects)</term><term>Mutation (genetics)</term><term>Pericytes (drug effects)</term><term>Pericytes (pathology)</term><term>Phosphatidylinositol 3-Kinases (genetics)</term><term>Receptor, TIE-2 (metabolism)</term><term>Sirolimus (pharmacology)</term><term>Vascular Malformations (enzymology)</term><term>Vascular Malformations (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Anomalies vasculaires (enzymologie)</term><term>Anomalies vasculaires (génétique)</term><term>Cellules endothéliales ()</term><term>Cellules endothéliales (anatomopathologie)</term><term>Humains</term><term>Mosaïcisme ()</term><term>Mutation (génétique)</term><term>Mésoderme ()</term><term>Mésoderme (anatomopathologie)</term><term>Mésoderme (embryologie)</term><term>Phosphatidylinositol 3-kinases (génétique)</term><term>Prolifération cellulaire ()</term><term>Péricytes ()</term><term>Péricytes (anatomopathologie)</term><term>Récepteur TIE-2 (métabolisme)</term><term>Sirolimus (pharmacologie)</term><term>Souris de lignée C57BL</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Phosphatidylinositol 3-Kinases</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Cellules endothéliales</term><term>Mésoderme</term><term>Péricytes</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Proliferation</term><term>Endothelial Cells</term><term>Mesoderm</term><term>Mosaicism</term><term>Pericytes</term></keywords><keywords scheme="MESH" qualifier="embryologie" xml:lang="fr"><term>Mésoderme</term></keywords><keywords scheme="MESH" qualifier="embryology" xml:lang="en"><term>Mesoderm</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Anomalies vasculaires</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Vascular Malformations</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Mutation</term><term>Vascular Malformations</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Anomalies vasculaires</term><term>Mutation</term><term>Phosphatidylinositol 3-kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Receptor, TIE-2</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Récepteur TIE-2</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Endothelial Cells</term><term>Mesoderm</term><term>Pericytes</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Sirolimus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Sirolimus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Mice, Inbred C57BL</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules endothéliales</term><term>Humains</term><term>Mosaïcisme</term><term>Mésoderme</term><term>Prolifération cellulaire</term><term>Péricytes</term><term>Souris de lignée C57BL</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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