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...

Descripción completa

Detalles Bibliográficos
Autores: Kobialka, P, Sabata, H, Vilalta, O, Gouveia, L, Angulo-Urarte, A, Muixi, L, Zanoncello, J, Munoz-Aznar, O, Olaciregui, NG, Fanlo, L, Esteve-Codina, A, Lavarino, C, Javierre, BM, Celis, V, Rovira, C, Lopez-Fernandez, S, Baselga, E, Mora, J, Castillo, SD, Graupera, M
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p11204
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11204
http://hdl.handle.net/10230/54619
Access Level:acceso abierto
Palabra clave:AKT
angiogenesis
endothelial cell
PI3K
vascular malformations
id ES_f79fcf4ad4d459e26e6df91d8a04843c
oai_identifier_str oai:iibsantpau.fundanetsuite.com:p11204
network_acronym_str ES
network_name_str España
repository_id_str
spelling The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertibKobialka, PSabata, HVilalta, OGouveia, LAngulo-Urarte, AMuixi, LZanoncello, JMunoz-Aznar, OOlaciregui, NGFanlo, LEsteve-Codina, ALavarino, CJavierre, BMCelis, VRovira, CLopez-Fernandez, SBaselga, EMora, JCastillo, SDGraupera, MAKTangiogenesisendothelial cellPI3Kvascular malformationsLow-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.WILEY2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11204http://hdl.handle.net/10230/54619EMBO Molecular MedicineISSN: 17574676ISSNe: 17574684reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p112042026-06-14T12:41:47Z
dc.title.none.fl_str_mv 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
spellingShingle The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib
Kobialka, P
AKT
angiogenesis
endothelial cell
PI3K
vascular malformations
title_short 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_sort The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib
dc.creator.none.fl_str_mv Kobialka, P
Sabata, H
Vilalta, O
Gouveia, L
Angulo-Urarte, A
Muixi, L
Zanoncello, J
Munoz-Aznar, O
Olaciregui, NG
Fanlo, L
Esteve-Codina, A
Lavarino, C
Javierre, BM
Celis, V
Rovira, C
Lopez-Fernandez, S
Baselga, E
Mora, J
Castillo, SD
Graupera, M
author Kobialka, P
author_facet Kobialka, P
Sabata, H
Vilalta, O
Gouveia, L
Angulo-Urarte, A
Muixi, L
Zanoncello, J
Munoz-Aznar, O
Olaciregui, NG
Fanlo, L
Esteve-Codina, A
Lavarino, C
Javierre, BM
Celis, V
Rovira, C
Lopez-Fernandez, S
Baselga, E
Mora, J
Castillo, SD
Graupera, M
author_role author
author2 Sabata, H
Vilalta, O
Gouveia, L
Angulo-Urarte, A
Muixi, L
Zanoncello, J
Munoz-Aznar, O
Olaciregui, NG
Fanlo, L
Esteve-Codina, A
Lavarino, C
Javierre, BM
Celis, V
Rovira, C
Lopez-Fernandez, S
Baselga, E
Mora, J
Castillo, SD
Graupera, M
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv AKT
angiogenesis
endothelial cell
PI3K
vascular malformations
topic AKT
angiogenesis
endothelial cell
PI3K
vascular malformations
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.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11204
http://hdl.handle.net/10230/54619
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11204
http://hdl.handle.net/10230/54619
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv WILEY
publisher.none.fl_str_mv WILEY
dc.source.none.fl_str_mv EMBO Molecular Medicine
ISSN: 17574676
ISSNe: 17574684
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869424899951427584
score 15,812429

Similares en LA Referencia