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The Circadian System Is Essential for the Crosstalk of VEGF-Notch-mediated Endothelial Angiogenesis in Ischemic Stroke

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Abstract

Ischemic stroke is a major public health problem worldwide. Although the circadian clock is involved in the process of ischemic stroke, the exact mechanism of the circadian clock in regulating angiogenesis after cerebral infarction remains unclear. In the present study, we determined that environmental circadian disruption (ECD) increased the stroke severity and impaired angiogenesis in the rat middle cerebral artery occlusion model, by measuring the infarct volume, neurological tests, and angiogenesis-related protein. We further report that Bmal1 plays an irreplaceable role in angiogenesis. Overexpression of Bmal1 promoted tube-forming, migration, and wound healing, and upregulated the vascular endothelial growth factor (VEGF) and Notch pathway protein levels. This promoting effect was reversed by the Notch pathway inhibitor DAPT, according to the results of angiogenesis capacity and VEGF pathway protein level. In conclusion, our study reveals the intervention of ECD in angiogenesis in ischemic stroke and further identifies the exact mechanism by which Bmal1 regulates angiogenesis through the VEGF-Notch1 pathway.

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Acknowledgements

We would like to thank researcher Ping Li for excellent technical support. This work was supported by the National Natural Science Foundation for Young Scholars of China (82004346 and 82104766), the Natural Science Foundation of Hunan Province (2021JJ30521 and 2021JJ40424), the Open Fund for the First-class Discipline of Integrated Traditional Chinese and Western Medicine of Hunan University of Chinese Medicine (2020ZXYJH38 and 2020ZXYJH39), Natural Science Foundation of Changsha (kq2208202), and the University-level Fund Project of Hunan University of Chinese Medicine (2021XJJJ039).

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  1. Department of Neurology, The First Hospital of Hunan University of Chinese Medicine, Changsha, 410007, China

    Yuxing Zhang, Chun Guo, Ying Zhang, Fukang Zeng, Zhong Li, Desheng Zhou & Lijuan Liu

  2. Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Changsha, 410208, China

    Yuxing Zhang & Fukang Zeng

  3. Hunan University of Chinese Medicine, Changsha, 410006, China

    Yuxing Zhang, Xin Zhao, Ying Zhang, Fukang Zeng, Qian Yin & Le Shao

  4. Laboratory of Prevention and Transformation of Major Diseases in Internal Medicine of Traditional Chinese Medicine, Changsha, 410007, China

    Le Shao

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  1. Yuxing Zhang
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Zhang, Y., Zhao, X., Guo, C. et al. The Circadian System Is Essential for the Crosstalk of VEGF-Notch-mediated Endothelial Angiogenesis in Ischemic Stroke. Neurosci. Bull. 39, 1375–1395 (2023). https://doi.org/10.1007/s12264-023-01042-9

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