Long-term continuous corticosterone treatment decreases VEGF receptor-2 expression in frontal cortex

Stress and increased glucocorticoid levels are associated with many neuropsychiatric disorders including schizophrenia and depression. Recently, the role of vascular endothelial factor receptor-2 (VEGFR2/Flk1) signaling has been implicated in stress-mediated neuroplasticity. However, the mechanism o...

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Bibliographic Details
Published in:PloS one 2011-05, Vol.6 (5), p.e20198
Main Authors: Howell, Kristy R, Kutiyanawalla, Ammar, Pillai, Anilkumar
Format: Article
Language:English
Subjects:
Aged
AKT protein
Angiogenesis
Animals
Antidepressants
Apoptosis
Brain
Brain research
Calcium
Calcium - metabolism
Case-Control Studies
Cells, Cultured
Cortex (frontal)
Corticosterone
Corticosterone - administration & dosage
Corticosterone - blood
Corticosterone - pharmacology
Depression (Mood disorder)
Dopamine
Down-Regulation - drug effects
Drosophila melanogaster
Exposure
Female
Frontal Lobe - cytology
Frontal Lobe - drug effects
Frontal Lobe - metabolism
Frontal Lobe - pathology
Gene expression
Gene Expression Regulation - drug effects
Glucocorticoids
Health behavior
Health sciences
Humans
Insects
Kinases
Male
Medical research
Medicine
Mental depression
Mental disorders
Mice
Nervous system diseases
Neural plasticity
Neurons
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Neurons - pathology
Neurophysiology
Norwood, Charlie
Phosphoproteins - metabolism
Prefrontal cortex
Prefrontal Cortex - cytology
Prefrontal Cortex - pathology
Proteins
Proto-Oncogene Proteins c-akt - metabolism
Psychiatry
PTEN Phosphohydrolase - metabolism
PTEN protein
Receptors, Glucocorticoid - metabolism
Rodents
Schizophrenia
Schizophrenia - pathology
Signal transduction
Signal Transduction - drug effects
Signaling
Steroids (Organic compounds)
Stress
Stress (Psychology)
Stresses
Studies
Time Factors
TOR protein
TOR Serine-Threonine Kinases - metabolism
Trends
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - metabolism
Vascular Endothelial Growth Factor Receptor-2 - metabolism
Vascular endothelial growth factor receptors
Veterans
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Summary:Stress and increased glucocorticoid levels are associated with many neuropsychiatric disorders including schizophrenia and depression. Recently, the role of vascular endothelial factor receptor-2 (VEGFR2/Flk1) signaling has been implicated in stress-mediated neuroplasticity. However, the mechanism of regulation of VEGF/Flk1 signaling under long-term continuous glucocorticoid exposure has not been elucidated. We examined the possible effects of long-term continuous glucocorticoid exposure on VEGF/Flk1 signaling in cultured cortical neurons in vitro, mouse frontal cortex in vivo, and in post mortem human prefrontal cortex of both control and schizophrenia subjects. We found that long-term continuous exposure to corticosterone (CORT, a natural glucocorticoid) reduced Flk1 protein levels both in vitro and in vivo. CORT treatment resulted in alterations in signaling molecules downstream to Flk1 such as PTEN, Akt and mTOR. We demonstrated that CORT-induced changes in Flk1 levels are mediated through glucocorticoid receptor (GR) and calcium. A significant reduction in Flk1-GR interaction was observed following CORT exposure. Interestingly, VEGF levels were increased in cortex, but decreased in serum following CORT treatment. Moreover, significant reductions in Flk1 and GR protein levels were found in postmortem prefrontal cortex samples from schizophrenia subjects. The alterations in VEGF/Flk1 signaling following long-term continuous CORT exposure represents a molecular mechanism of the neurobiological effects of chronic stress.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0020198