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

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.

• Authors: Yue Zhang, Gina Hong, Kin Sing Stephen Lee, Bruce D Hammock, Debebe Gebremedhin, David R Harder, Raymond C Koehler, Adam Sapirstein
• Journal: Journal of neurochemistry (J Neurochem) Vol. 140 Issue 5 Pg. 814-825 (03 2017) ISSN: 1471-4159 [Electronic] England
• PMID: 28002622 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 International Society for Neurochemistry.

Chemical References

• Culture Media, Conditioned
• Enzyme Inhibitors
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, rat
• Receptors, Vascular Endothelial Growth Factor
• Oncogene Protein v-akt
• Epoxide Hydrolases
• Glucose

Topics

• Animals
• Astrocytes (drug effects, metabolism)
• Cell Hypoxia (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Culture Media, Conditioned
• Enzyme Inhibitors (pharmacology)
• Epoxide Hydrolases (antagonists & inhibitors)
• Female
• Glucose (deficiency)
• Neurons (drug effects, metabolism)
• Oncogene Protein v-akt (metabolism)
• Phosphorylation
• Pregnancy
• Rats
• Rats, Sprague-Dawley
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor A (metabolism)