The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib.
Piotr KobialkaHelena SabataOdena VilaltaLeonor GouveiaAna Angulo-UrarteLaia MuixíJasmina ZanoncelloOscar Muñoz-AznarNagore G OlacireguiLucia FanloAnna Esteve-CodinaCinzia LavarinoBiola M JavierreVeronica CelisCarlota RoviraSusana López-FernándezEulalia BaselgaJaume Catala-MoraSandra D CastilloMariona GrauperaPublished in: EMBO molecular medicine (2022)
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.
Keyphrases
- endothelial cells
- cell proliferation
- signaling pathway
- clinical trial
- high glucose
- vascular endothelial growth factor
- mesenchymal stem cells
- cell therapy
- nitric oxide
- atrial fibrillation
- spinal cord
- spinal cord injury
- cell cycle
- induced pluripotent stem cells
- genome wide
- electronic health record
- mouse model
- open label
- protein kinase
- single molecule
- pluripotent stem cells