مورد إلكتروني
Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation
| العنوان: | Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation |
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| بيانات النشر: | Springer Science and Business Media B.V. 2023 |
| تفاصيل مُضافة: | Huo, Ran Yang, Yingxi Sun, Yingfan Zhou, Qiuxia Zhao, Shaozhi Mo, Zongchao Xu, Hongyuan Wang, Jie Weng, Jiancong Jiao, Yuming Zhang, Junze He, Qiheng Wang, Shuo Zhao, Jizong Wang, Jiguang Cao, Yong |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Cerebral cavernous malformations (CCMs) refer to a common vascular abnormality that affects up to 0.5% of the population. A somatic gain-of-function mutation in MAP3K3 (p.I441M) was recently reported in sporadic CCMs, frequently accompanied by somatic activating PIK3CA mutations in diseased endothelium. However, the molecular mechanisms of these driver genes remain elusive. In this study, we performed whole-exome sequencing and droplet digital polymerase chain reaction to analyze CCM lesions and the matched blood from sporadic patients. 44 of 94 cases harbored mutations in KRIT1/CCM2 or MAP3K3, of which 75% were accompanied by PIK3CA mutations (P = 0.006). AAV-BR1-mediated brain endothelial-specific MAP3K3I441M overexpression induced CCM-like lesions throughout the brain and spinal cord in adolescent mice. Interestingly, over half of lesions disappeared at adulthood. Single-cell RNA sequencing found significant enrichment of the apoptosis pathway in a subset of brain endothelial cells in MAP3K3I441M mice compared to controls. We then demonstrated that MAP3K3I441M overexpression activated p38 signaling that is associated with the apoptosis of endothelial cells in vitro and in vivo. In contrast, the mice simultaneously overexpressing PIK3CA and MAP3K3 mutations had an increased number of CCM-like lesions and maintained these lesions for a longer time compared to those with only MAP3K3I441M. Further in vitro and in vivo experiments showed that activating PI3K signaling increased proliferation and alleviated apoptosis of endothelial cells. By using AAV-BR1, we found that MAP3K3I441M mutation can provoke CCM-like lesions in mice and the activation of PI3K signaling significantly enhances and maintains these lesions, providing a preclinical model for the further mechanistic and therapeutic study of CCMs. © 2023, The Author(s), under exclusive licence to Springer Nature B.V. |
| مصطلحات الفهرس: | Cerebral Cavernous Malformations, MAP3K3 p.I441M, Mouse model, PIK3CA mutation, Article |
| URL: | |
| الإتاحة: | Open access content. Open access content |
| ملاحظة: | English |
| أرقام أخرى: | HNK oai:repository.hkust.edu.hk:1783.1-124347 Angiogenesis, January 2023 0969-6970 1573-7209 1376638053 |
| المصدر المساهم: | HONG KONG UNIV OF SCI & TECH, THE From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1376638053 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |