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Astrocytes Regulate Angiogenesis Through the Jagged1-Mediated Notch1 Pathway After Status Epilepticus

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Abstract

Vascular disruptions including blood–brain barrier breakdown and pathologic angiogenesis contribute to the development of epilepsy in normal brains. The Notch signaling pathway is activated in response to seizure activity, and its activation promotes seizures, although its exact role in angiogenesis is poorly understood. Here, we have examined the role of Notch signaling in angiogenesis in a kainic acid-induced mouse model of epilepsy. We show that following seizures, expression of the Notch ligand Jagged1 in the hippocampus is upregulated in astrocytes and levels of activated Notch1 are increased in endothelial cells. Using an in vitro model of angiogenesis, we provide evidence that brain endothelial tube formation is promoted in the presence of astrocytes. Isolated primary brain endothelial cells develop significantly longer vascular sprouts when cultured in the presence of astrocytes. Notch1 signaling is activated in brain endothelial cells cocultured with astrocytes, and astrocytic Jagged1 expression is required for angiogenic enhancement, as shown by the inhibitory effect of Jagged1 small interfering RNA (siRNA) expression in astrocytes on endothelial cell vascular sprouting in vitro. Therapies targeting the Jagged1/Notch1 signaling pathway may therefore be effective in limiting aberrant angiogenesis following status epilepticus.

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Acknowledgments

This work was supported by grant 2009-2-264 from Chongqing Municipal Health Bureau Research Fund, grant cstc2012gg-yyjs0838 from Chongqing Science and Technology Commission scientific and technological projects, and the Chongqing Natural Science Foundation (2008-4-174).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Neurosurgery, Children’s Hospital of Chongqing Medical University, 136 Zhongshan 2nd Road, Yuzhong, Chongqing, 400014, China

    Xuan Zhai, Ping Liang, Yingliang Li, Lusheng Li, Yudong Zhou, Xuanxuan Wu & Jinmu Deng

  2. Department of Neurology, Children’s Hospital of Chongqing Medical University, 136 Zhongshan 2nd Road, Yuzhong, Chongqing, 400014, China

    Li Jiang

  3. Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Xuan Zhai, Ping Liang, Yingliang Li, Lusheng Li, Yudong Zhou, Xuanxuan Wu, Jinmu Deng & Li Jiang

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  1. Xuan Zhai
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Correspondence to Xuan Zhai or Li Jiang.

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Zhai, X., Liang, P., Li, Y. et al. Astrocytes Regulate Angiogenesis Through the Jagged1-Mediated Notch1 Pathway After Status Epilepticus. Mol Neurobiol 53, 5893–5901 (2016). https://doi.org/10.1007/s12035-015-9492-8

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  • DOI: https://doi.org/10.1007/s12035-015-9492-8

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