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 |
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| Authors: | Piotr Kobialka, Helena Sabata, Odena Vilalta, Leonor Gouveia, Ana Angulo‐Urarte, Laia Muixí, Jasmina Zanoncello, Oscar Muñoz‐Aznar, Nagore G Olaciregui, Lucia Fanlo, Anna Esteve‐Codina, Cinzia Lavarino, Biola M Javierre, Veronica Celis, Carlota Rovira, Susana López‐Fernández, Eulàlia Baselga, Jaume Mora, Sandra D Castillo, Mariona Graupera |
| Source: | EMBO Molecular Medicine, Vol 14, Iss 7, Pp 1-19 (2022) |
| Publisher Information: | Springer Nature, 2022. |
| Publication Year: | 2022 |
| Collection: | LCC:Medicine (General) LCC:Genetics |
| Subject Terms: | AKT, angiogenesis, endothelial cell, PI3K, vascular malformations, Medicine (General), R5-920, Genetics, QH426-470 |
| More Details: | Abstract 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 Pik3caH1047R 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1757-4676 1757-4684 |
| Relation: | https://doaj.org/toc/1757-4676; https://doaj.org/toc/1757-4684 |
| DOI: | 10.15252/emmm.202115619 |
| Access URL: | https://doaj.org/article/40a39a76675043aaaccc4230021e9c4d |
| Accession Number: | edsdoj.40a39a76675043aaaccc4230021e9c4d |
| Database: | Directory of Open Access Journals |
| ISSN: | 17574676 17574684 |
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| DOI: | 10.15252/emmm.202115619 |
| Published in: | EMBO Molecular Medicine |
| Language: | English |