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mTOR-FABP4 signal is activated in brain arteriovenous malformations in humans

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Abstract

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.

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Availability of data and material

Data will be shared with qualified investigators upon request; please contact zhaoyuanli@126.com.

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Acknowledgements

Debin Yan wants to thank the invaluable support received from Kaihong Zheng over the years.

Funding

This study was funded by the National Natural Science Foundation of China (H0906 81571110 and 82071302 to Yuanli Zhao), National Key Research and Development Program of China (2020YFC2004701 to Xiaolin Chen), Beijing Natural Science Foundation (7204253 to Qiang Hao), Beijing Municipal Hospital Cultivation Program (pX2020023 to Qiang Hao), and Hainan Science and Technology Project (ZDYF2021SHFZ111 to Hao Peng).

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Authors and Affiliations

  1. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Debin Yan, Qiang Hao, Yu Chen, Zhipeng Li, Haibin Zhang, Kexin Yuan, Runting Li, Ruinan Li, Yahui Zhao, Ke Wang, Dong Zhang, Xiaolin Chen & Yuanli Zhao

  2. Department of Neurosurgery, Peking University International Hospital, Peking University, Beijing, China

    Yuanli Zhao

  3. China National Clinical Research Center for Neurological Diseases, Beijing, China

    Yuanli Zhao

  4. Stroke Center, Beijing Institute for Brain Disorders, Beijing, China

    Yuanli Zhao

  5. Beijing Key Laboratory of Translation Medicine for Cerebrovascular Disease, Beijing, China

    Yuanli Zhao

  6. Beijing Translational Engineering Enter for 3D Printer in Clinical Neuroscience, Beijing, China

    Yuanli Zhao

  7. Hainan General Hospital, Hainan, China

    Hao Peng

Authors
  1. Debin Yan
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  2. Qiang Hao
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  3. Yu Chen
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  12. Dong Zhang
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  13. Xiaolin Chen
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  14. Yuanli Zhao
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Contributions

YLZ designed the whole experiment. DBY and QH participated in the whole procedure. DZ and XLC provided the AVM tissues, YC, ZPL, HBZ, KXY, RNL, RTL, YHZ, and HP took part in the collection of AVM tissues and discussion. All authors consent to participate and publication.

Corresponding authors

Correspondence to Dong Zhang, Xiaolin Chen or Yuanli Zhao.

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Ethics approval

This experiment was approved by the Beijing Tian Tan Hospital Ethics Committee (Beijing, China) (KYSQ 2020–038-01).

Conflict of interest

The authors declare no competing interests.

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Debin Yan and Qiang Hao have contributed equally to this work.

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Yan, D., Hao, Q., Chen, Y. et al. mTOR-FABP4 signal is activated in brain arteriovenous malformations in humans. J Mol Med 100, 1287–1297 (2022). https://doi.org/10.1007/s00109-022-02237-9

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  • DOI: https://doi.org/10.1007/s00109-022-02237-9

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