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J Neurochem. 2017 Mar;140(5):814-825. doi: 10.1111/jnc.13933. Epub 2017 Jan 23.

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

Author information

1
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
2
Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3
Department of Entomology and Nematology and UCD Comprehensive Cancer Center, University of California, Davis, California, USA.
4
Department of Physiology and the Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
5
Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin.

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.

KEYWORDS:

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

PMID:
28002622
PMCID:
PMC5310989
DOI:
10.1111/jnc.13933
[Indexed for MEDLINE]
Free PMC Article

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