title: 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.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.|Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Gina
authors.initials: G
authors.lastname: Hong
authors.affiliation: Department of Entomology and Nematology and UCD Comprehensive Cancer Center, University of California, Davis, California, USA.
authors.forename: Kin Sing Stephen
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Entomology and Nematology and UCD Comprehensive Cancer Center, University of California, Davis, California, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Physiology and the Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Debebe
authors.initials: D
authors.lastname: Gebremedhin
authors.affiliation: Department of Physiology and the Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin.|Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin.
authors.forename: David R
authors.initials: DR
authors.lastname: Harder
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Adam
authors.initials: A
authors.lastname: Sapirstein
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D005260:Female; D005947:Glucose / Q000172:deficiency*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D040262:Receptors, Vascular Endothelial Growth Factor; D051058:Oncogene Protein v-akt; D004851:Epoxide Hydrolases; D005947:Glucose
keywords: Akt; astrocyte; epoxide hydrolase; epoxyeicosatrienoic acid; oxygen-glucose deprivation; vascular endothelial growth factor