Vascular Endothelia Growth Factor and its Receptor VEGFR2 Regulate Synaptic Protein Levels in Rat Hippocampal Neurons
Item
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Title
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Vascular Endothelia Growth Factor and its Receptor VEGFR2 Regulate Synaptic Protein Levels in Rat Hippocampal Neurons
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Identifier
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d_2009_2013:b908b3f4a655:11422
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identifier
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11823
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Creator
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Cao, Qin,
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Contributor
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Patricia Rockwell
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Date
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2012
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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 | Molecular biology | PSD-95 | Synapsin | Synaptic protein | Synaptophysin | VEGF | VEGFR2
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Abstract
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Vascular endothelial growth factor (VEGF) is a well-established angiogenic factor which also elicits protective and stimulatory effects on neuronal function. Recent studies suggest that VEGF signaling plays a critical role in modulating synaptic plasticity and enhances excitatory synaptic transmission in the hippocampus. Other growth factors including brain-derived neurotrophic factor (BDNF) and insulin have been shown to regulate synaptic protein levels to stimulate neural communication but it remains unclear how VEGF participates in synapse function at the molecular level. The notion that VEGF would also modulate synaptic protein levels in differentiated hippocampal neurons has not been explored. Therefore, this work addressed whether VEGF exhibits neurotropic properties in mature rat hippocampal neurons by modulating the postsynaptic protein PSD-95 and protecting against the stress induced by nutritional deprivation. The results show that VEGF signals an increase in cell viability and increases the levels of presynaptic (synaptophysin and synapsin I) and postsynaptic (PSD-95) proteins through its cognate receptor VEGFR2. VEGF signals these events via autocrine and paracrine mechanisms. Moreover, VEGF regulates PSD-95 protein levels and synapse numbers along dendrites through the PI3K/Akt/mTOR pathway. Additional studies showed that inhibition of the Rho-associated protein kinase (ROCK) increased PSD-95 protein levels which were attenuated by VEGFR2 inhibition. Furthermore, ROCK inhibition enhanced VEGF-mediated synapse formation, survival and neurite extension. Accordingly, these findings suggest that ROCK serves as a negative regulator of VEGF signaling in mature primary hippocampal neurons. Collectively, this study revealed a novel signaling mechanism for VEGF/VEGFR-2 pathway that may function in its reported capacity to stimulate synaptic transmission. These findings implicate VEGF signaling as a potential therapeutic strategy to prevent or hinder synaptic loss in neurodegenerative disorders.
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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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Biology
