Inhibition of soluble epoxide hydrolase augments astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen-glucose deprivation. J Neurochem 2017 Mar;140(5):814-825
Date
12/22/2016Pubmed ID
28002622Pubmed Central ID
PMC5310989DOI
10.1111/jnc.13933Scopus ID
2-s2.0-85013779052 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
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.
Author List
Zhang Y, Hong G, Lee KS, Hammock BD, Gebremedhin D, Harder DR, Koehler RC, Sapirstein AMESH terms used to index this publication - Major topics in bold
AnimalsAstrocytes
Cell Hypoxia
Cell Survival
Cells, Cultured
Culture Media, Conditioned
Enzyme Inhibitors
Epoxide Hydrolases
Female
Glucose
Neurons
Oncogene Protein v-akt
Phosphorylation
Pregnancy
Rats
Rats, Sprague-Dawley
Receptors, Vascular Endothelial Growth Factor
Signal Transduction
Vascular Endothelial Growth Factor A
