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The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib
Low‐flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of r...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260211/ https://www.ncbi.nlm.nih.gov/pubmed/35695059 http://dx.doi.org/10.15252/emmm.202115619 |
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author | Kobialka, Piotr Sabata, Helena Vilalta, Odena Gouveia, Leonor Angulo‐Urarte, Ana Muixí, Laia Zanoncello, Jasmina Muñoz‐Aznar, Oscar Olaciregui, Nagore G Fanlo, Lucia Esteve‐Codina, Anna Lavarino, Cinzia Javierre, Biola M Celis, Veronica Rovira, Carlota López‐Fernández, Susana Baselga, Eulàlia Mora, Jaume Castillo, Sandra D Graupera, Mariona |
author_facet | Kobialka, Piotr Sabata, Helena Vilalta, Odena Gouveia, Leonor Angulo‐Urarte, Ana Muixí, Laia Zanoncello, Jasmina Muñoz‐Aznar, Oscar Olaciregui, Nagore G Fanlo, Lucia Esteve‐Codina, Anna Lavarino, Cinzia Javierre, Biola M Celis, Veronica Rovira, Carlota López‐Fernández, Susana Baselga, Eulàlia Mora, Jaume Castillo, Sandra D Graupera, Mariona |
author_sort | Kobialka, Piotr |
collection | PubMed |
description | Low‐flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we demonstrate that the Pik3ca(H1047R) activating mutation in endothelial cells triggers a transcriptome rewiring that leads to enhanced cell proliferation. We describe a new reproducible preclinical in vivo model of PI3K‐driven vascular malformations using the postnatal mouse retina. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that the AKT inhibitor miransertib both prevents and induces the regression of PI3K‐driven vascular malformations. We confirmed the efficacy of miransertib in isolated human endothelial cells with genotypes spanning most of human low‐flow vascular malformations. |
format | Online Article Text |
id | pubmed-9260211 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92602112022-07-11 The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib Kobialka, Piotr Sabata, Helena Vilalta, Odena Gouveia, Leonor Angulo‐Urarte, Ana Muixí, Laia Zanoncello, Jasmina Muñoz‐Aznar, Oscar Olaciregui, Nagore G Fanlo, Lucia Esteve‐Codina, Anna Lavarino, Cinzia Javierre, Biola M Celis, Veronica Rovira, Carlota López‐Fernández, Susana Baselga, Eulàlia Mora, Jaume Castillo, Sandra D Graupera, Mariona EMBO Mol Med Articles Low‐flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we demonstrate that the Pik3ca(H1047R) activating mutation in endothelial cells triggers a transcriptome rewiring that leads to enhanced cell proliferation. We describe a new reproducible preclinical in vivo model of PI3K‐driven vascular malformations using the postnatal mouse retina. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that the AKT inhibitor miransertib both prevents and induces the regression of PI3K‐driven vascular malformations. We confirmed the efficacy of miransertib in isolated human endothelial cells with genotypes spanning most of human low‐flow vascular malformations. John Wiley and Sons Inc. 2022-06-13 /pmc/articles/PMC9260211/ /pubmed/35695059 http://dx.doi.org/10.15252/emmm.202115619 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Kobialka, Piotr Sabata, Helena Vilalta, Odena Gouveia, Leonor Angulo‐Urarte, Ana Muixí, Laia Zanoncello, Jasmina Muñoz‐Aznar, Oscar Olaciregui, Nagore G Fanlo, Lucia Esteve‐Codina, Anna Lavarino, Cinzia Javierre, Biola M Celis, Veronica Rovira, Carlota López‐Fernández, Susana Baselga, Eulàlia Mora, Jaume Castillo, Sandra D Graupera, Mariona The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib |
title | The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib |
title_full | The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib |
title_fullStr | The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib |
title_full_unstemmed | The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib |
title_short | The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib |
title_sort | onset of pi3k‐related vascular malformations occurs during angiogenesis and is prevented by the akt inhibitor miransertib |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260211/ https://www.ncbi.nlm.nih.gov/pubmed/35695059 http://dx.doi.org/10.15252/emmm.202115619 |
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