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.

中文翻译：

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PI3K 相关血管畸形的发作发生在血管生成过程中，可通过 AKT 抑制剂 miransertib 预防

低流量血管畸形是由异常血管组成的先天性过度生长，可能导致不同器官的疼痛、出血和阻塞。这些疾病是由内皮中的致癌突变引起的，这些突变导致 PI3K/AKT 通路的过度激活。缺乏可靠的体内临床前数据阻碍了针对这些疾病的特定分子疗法的开发和转化为临床试验。在这里，我们证明了内皮细胞中的Pik3ca ^H1047R激活突变触发了转录组重新布线，从而导致细胞增殖增强。我们描述了一种新的可重复的临床前体内使用产后小鼠视网膜的 PI3K 驱动的血管畸形模型。我们表明，激活Pik3ca突变引起的血管畸形的发病机制需要活跃的血管生成。使用该模型，我们证明 AKT 抑制剂 miransertib 既可预防又可诱导 PI3K 驱动的血管畸形的消退。我们证实了 miransertib 在分离的人类内皮细胞中的功效，其基因型涵盖了大多数人类低流量血管畸形。