Inhibition of soluble epoxide hydrolase augments astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen‐glucose deprivation. Issue 5 (23rd January 2017)

• Record Type: Journal Article
• Authors: Zhang, Yue; Hong, Gina; Lee, Kin Sing Stephen; Hammock, Bruce D.; Gebremedhin, Debebe; Harder, David R.; Koehler, Raymond C.; Sapirstein, Adam
• Is Part Of: Journal of neurochemistry. Volume 140:Issue 5(2017)
• Page Start: 814
• Page End: 825
• Publication Date: 2017-01-23
• Subjects: Akt -- astrocyte -- epoxide hydrolase -- epoxyeicosatrienoic acid -- oxygen‐glucose deprivation -- vascular endothelial growth factor; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.13933
• Languages: English
• ISSNs: 0022-3042

Abstract

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. Abstract : Inhibition of soluble epoxide hydrolase after oxygen‐glucose deprivation in astrocytes stabilizes epoxyeicosatrienoic acids, which then augment the release of VEGF. Exposure of neurons to oxygen‐glucose deprivation followed by the conditioned astrocyte medium increases neuronal phosphorylated Akt through VEGF receptor‐2 signaling and leads to increased neuronal survival, thereby providing evidence of one way by which astrocytes can be leveraged for neuroprotection.