Vascular endothelial growth factor receptor-3 regulates astroglial glutamate transporter-1 expression via mTOR activation in reactive astrocytes following pilocarpine-induced status epilepticus

Kyoung Hoon Jeong, Kyung Ok Cho, Mun Yong Lee, Seong Yun Kim, Won Joo Kim

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Recent evidence has shown that the vascular endothelial growth factor (VEGF) system plays a crucial role in several neuropathological processes. We previously reported an upregulation of VEGF-C and its receptor, VEGFR-3, in reactive astrocytes after the onset of status epilepticus (SE). However, it remains unknown, which molecules act as downstream signals following VEGFR-3 upregulation, and are involved in reactive astrogliosis after SE. Therefore, we investigated whether VEGFR-3 upregulation within reactive astrocytes is associated with the activation of mammalian target of rapamycin (mTOR) signaling, which we confirmed by assaying for the phosphorylated form of S6 protein (pS6), and whether VEGFR-3-mediated mTOR activation induces astroglial glutamate transporter-1 (GLT-1) expression in the hippocampus after pilocarpine-induced SE. We found that spatiotemporal expression of pS6 was consistent with VEGFR-3 expression in the hippocampus after SE, and that both pS6 and VEGFR-3 were highly expressed in SE-induced reactive astrocytes. Treatment with the mTOR inhibitor rapamycin decreased astroglial VEGFR-3 expression and GLT-1 expression after SE. Treatment with a selective inhibitor for VEGFR-3 attenuated astroglial pS6 expression as well as suppressed GLT-1 expression and astroglial reactivity in the hippocampus after SE. These findings demonstrate that VEGFR-3-mediated mTOR activation could contribute to the regulation of GLT-1 expression in reactive astrocytes during the subacute phase of epilepsy. In conclusion, the present study suggests that VEGFR-3 upregulation in reactive astrocytes may play a role in preventing hyperexcitability induced by continued seizure activity.

Original languageEnglish
Pages (from-to)296-309
Number of pages14
JournalGLIA
Volume69
Issue number2
DOIs
StatePublished - Feb 2021

Bibliographical note

Funding Information:
Ministry of Education, Grant/Award Numbers: NRF‐2018R1D1A1B07046708, NRF‐2018R1D1A1B07047059; National Research Foundation of Korea Funding information

Funding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF‐2018R1D1A1B07047059 and NRF‐2018R1D1A1B07046708). The authors would like thank Editage ( www.editage.co.kr ) for English language editing.

Publisher Copyright:
© 2020 Wiley Periodicals LLC

Keywords

  • glutamate transporter-1
  • mammalian target of rapamycin
  • reactive astrocytes
  • status epilepticus
  • vascular endothelial growth factor receptor-3

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