Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Hainan General Hospital, Hainan, China.
J Mol Med (Berl). 2022 Sep;100(9):1287-1297. doi: 10.1007/s00109-022-02237-9. Epub 2022 Jul 25.
Arteriovenous malformations (AVMs) are the most common types of cerebral vascular malformations, which are dynamic lesions with de novo growth potentials. The dysfunction of endothelial cells has been postulated to play a role in the pathogenesis of brain AVMs. mTOR-FABP4 signal enhances the angiogenic responses of endothelial cells and is not activated in the normal cerebral vasculature. Herein, we investigated the hypothesis that the mTOR-FABP4 signal may be activated in brain AVMs. The abundance of molecules in mTOR-FABP4 signal expression was detected by immunohistochemistry and Western blotting; special expressing cells were further characterized by double immunofluorescence using antibodies against various cell-specific markers. Next, several functional assays were performed to analyze the influence of the mTOR-FABP4 signal on proliferation, apoptosis, migration, and vascular tube formation of endothelial cells in human umbilical vein endothelial cells (HUVECs) using rapamycin and L-leucine. The expression of mTOR, p-mTOR, and FABP4 was increased in endothelial cells of human brain AVMs. Endothelial cell mTOR and p-mTOR expression were present in 70% and 55% of brain AVMs, respectively. Moreover, a population of FABP4-positive endothelial cells was detected in 80% of brain AVMs. The mTOR-FABP4 signal was activated and inhibited by L-leucine and rapamycin in HUVECs. The proliferation, apoptosis, migration, and vascular tube formation of endothelial cells could be inhibited by rapamycin. The mTOR-FABP4 signal was activated in human brain AVMs, and the mTOR-FABP4 signal was involved in proliferation, apoptosis, migration, and the vascular tube formation of endothelial cells. Taken together, whether rapamycin has therapeutic potential for treating human brain AVMs is worthy of further study. KEY MESSAGES : We confirmed that the mTOR- FABP4 pathway is activated in human brain arteriovenous malformations. We confirmed that mTOR signaling pathway affects endothelial cell function by regulating proliferation, migration, apoptosis, and tube formation of endothelial cell. Our study can provide theoretical support for mTOR pathway inhibitors in the treatment of human brain arteriovenous malformations.
动静脉畸形（AVMs）是最常见的脑血管畸形类型，是具有新生潜力的动态病变。内皮细胞功能障碍被认为在脑 AVM 的发病机制中起作用。mTOR-FABP4 信号增强内皮细胞的血管生成反应，在正常脑血管中未被激活。在此，我们研究了 mTOR-FABP4 信号可能在脑 AVM 中被激活的假设。通过免疫组织化学和 Western blot 检测 mTOR-FABP4 信号表达分子的丰度；使用针对各种细胞特异性标志物的抗体通过双免疫荧光进一步表征特殊表达细胞。接下来，使用雷帕霉素和 L-亮氨酸进行了几种功能测定，以分析 mTOR-FABP4 信号对人脐静脉内皮细胞（HUVEC）中内皮细胞增殖、凋亡、迁移和血管管形成的影响。人脑 AVM 内皮细胞中 mTOR、p-mTOR 和 FABP4 的表达增加。脑 AVM 中内皮细胞 mTOR 和 p-mTOR 的表达分别为 70%和 55%。此外，在 80%的脑 AVM 中检测到 FABP4 阳性内皮细胞群。L-亮氨酸和雷帕霉素激活和抑制 HUVEC 中的 mTOR-FABP4 信号。雷帕霉素可抑制内皮细胞的增殖、凋亡、迁移和血管管形成。mTOR-FABP4 信号在人脑 AVM 中被激活，mTOR-FABP4 信号参与内皮细胞的增殖、凋亡、迁移和血管管形成。总之，雷帕霉素是否对治疗人脑 AVM 具有治疗潜力值得进一步研究。
我们证实 mTOR-FABP4 通路在人脑动静脉畸形中被激活。我们证实 mTOR 信号通路通过调节内皮细胞的增殖、迁移、凋亡和管形成来影响内皮细胞的功能。我们的研究可为 mTOR 通路抑制剂治疗人脑动静脉畸形提供理论支持。
