VEGF signaling mediates neuroprotection against oxidative stress in hippocampal neurons in vivo and in vitro
Item
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Title
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VEGF signaling mediates neuroprotection against oxidative stress in hippocampal neurons in vivo and in vitro
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Identifier
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d_2009_2013:35526b517a02:11651
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identifier
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12268
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Creator
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Hao, Tianfeng,
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Contributor
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Patricia Rockwell
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Date
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2013
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Language
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English
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Publisher
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City University of New York.
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Subject
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Neurosciences | hippocampal neurons | mitochondrial dysfunction | oxidative stress | VEGF
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Abstract
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Vascular endothelia growth factor (VEGF) signaling through its cognate receptor VEGFR-2 has been shown to be neuroprotective against stressful stimuli including oxidative stress. Using a rat pilocarpine model of status epilepticus (SE), pilocarpine-induced SE was associated with the induction of the oxidative stress marker Heme oxygenase-1 (HO-1) and increased expression of the pro-inflammatory enzyme Cyclooxygenase-2 (COX-2). Treatments with exogenous VEGF attenuated the induction in HO-1 and the increase in COX-2 levels. Previous studies showed that VEGF protected hippocampal cell death in this model and these results suggest that oxidative stress and inflammation contribute to this neuronal loss. Similarly, in cultured hippocampal neurons, pilocarpine induced neuronal cell death accompanied with increased HO-1 expression, reactive oxygen species (ROS) production, caspase-3 cleavage and a loss of mitochondrial membrane potential (DeltaPsim) that were all suppressed by VEGF. To delineate the protective mechanisms associated with VEGF-mediated neuroprotection, VEGFR-2 inhibition was investigated with respect to oxidative stress in primary cultures of hippocampal neurons. Treatments with the pharmacological inhibitor SU1498 elicited a cytotoxicity that was prevented by the antioxidant N-acetyl-cysteine (NAC) and accompanied by induction of HO-1, cleavage of caspase-3, production of ROS together with a loss of DeltaPsim. Knockdown of VEGFR-2 by siRNA generated a similar pattern of ROS and DeltaPsim loss. Treatments with VEGF or VEGF-B prevented neurons from the cell death and mitochondrial dysfunction induced by SU1498 or siRNA, suggesting that a molecular switch occurs where both growth factors may signal through VEGFR-1 when VEGFR-2 activity is blocked. Consistent with a general role for pro-apoptotic BAD and anti-apoptotic Bcl-xL in neuronal cell death and oxidative stress, the phosphorylation of MEK/ERK1/2 and BAD (inactivation) and the protein levels of Bcl-xL that were attenuated by SU1498 were somewhat increased by VEGF. Our findings support a role for VEGF in signaling BAD inactivation and increased Bcl-xL as a specific mechanism that protects hippocampal neurons against oxidative stress. These findings also suggest that VEGF activates VEGFR-2 to protect neurons against oxidative stress but can signal through alternate receptors to serve the same function.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biochemistry
