Inhibition of soluble epoxide hydrolase augments astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen-glucose deprivation

Yue Zhang, Gina Hong, Kin Sing Stephen Lee, Bruce D. Hammock, Debebe Gebremedhin, David R. Harder, Raymond C. Koehler, Adam Sapirstein

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Epoxyeicosatrienoic acids (EETs) are synthesized in astrocytes, and inhibitors of soluble epoxide hydrolase (sEH), which hydrolyzes EETs, reduce infarct volume in ischemic stroke. Astrocytes can release protective neurotrophic factors, such as vascular endothelial growth factor (VEGF). We found that addition of sEH inhibitors to rat cultured astrocytes immediately after oxygen-glucose deprivation (OGD) markedly increased VEGF concentration in the medium 48 h later and the effect was blocked by an EET antagonist. The sEH inhibitors increased EET concentrations to levels capable of increasing VEGF. When the sEH inhibitors were removed from the medium at 48 h, the increase in VEGF persisted for an additional 48 h. Neurons exposed to OGD and subsequently to astrocyte medium previously conditioned with OGD plus sEH inhibitors showed increased phosphorylation of their VEGF receptor-2, less TUNEL staining, and increased phosphorylation of Akt, which was blocked by a VEGF receptor-2 antagonist. Our findings indicate that sEH inhibitors, applied to cultured astrocytes after an ischemia-like insult, can increase VEGF secretion. The released VEGF then enhances Akt-enabled cell survival signaling in neurons through activation of VEGF receptor-2 leading to less neuronal cell death. These results suggest a new strategy by which astrocytes can be leveraged to support neuroprotection. (Figure presented.).

Original languageEnglish (US)
Pages (from-to)814-825
Number of pages12
JournalJournal of Neurochemistry
Volume140
Issue number5
DOIs
StatePublished - Mar 1 2017

Keywords

  • Akt
  • astrocyte
  • epoxide hydrolase
  • epoxyeicosatrienoic acid
  • oxygen-glucose deprivation
  • vascular endothelial growth factor

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Zhang, Y., Hong, G., Lee, K. S. S., Hammock, B. D., Gebremedhin, D., Harder, D. R., Koehler, R. C., & Sapirstein, A. (2017). Inhibition of soluble epoxide hydrolase augments astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen-glucose deprivation. Journal of Neurochemistry, 140(5), 814-825. https://doi.org/10.1111/jnc.13933