Long-Term Continuous Corticosterone Treatment Decreases VEGF Receptor-2 Expression in Frontal Cortex

Kristy R Howell,Anilkumar Pillai,Ammar Kutiyanawalla,Thomas Burne

doi:10.1371/journal.pone.0020198

Kristy R Howell, Anilkumar Pillai + Show 2 more

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https://doi.org/10.1371/journal.pone.0020198

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Abstract

ObjectiveStress 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.Material and MethodsWe 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.ResultsWe 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.Conclusions The alterations in VEGF/Flk1 signaling following long-term continuous CORT exposure represents a molecular mechanism of the neurobiological effects of chronic stress.

Highlights

Stress and elevated glucocorticoid levels are known to be associated with a number of neuropsychiatric disorders including depression and schizophrenia
We demonstrated that CORT-induced changes in Flk1 levels are mediated through glucocorticoid receptor (GR) and calcium
Significant reductions in Flk1 and GR protein levels were found in postmortem prefrontal cortex samples from schizophrenia subjects

Summary

Introduction

Stress and elevated glucocorticoid levels are known to be associated with a number of neuropsychiatric disorders including depression and schizophrenia. Many of the effects of chronic stress are thought to be mediated by stress-induced increases in circulating levels of glucocorticoids [3,4]. Animal studies have shown a number of behavioral abnormalities similar to depression and anxiety following chronic administration of glucocorticoids [5,6,7]. VEGF is known to mediate its biological functions via activation of the protein tyrosine kinase receptors, VEGF receptor 1 (VEGFR-1/Flt1) and VEGFR-2 (KDR/Flk1) [9]. Flk has been shown to mediate VEGF action in neuronal functions [10,11] and activation of Flk allows the receptors to associate with various downstream effector molecules including phosphatidylinositol 3-kinase (PI3K) [12,13]. PI3K/Akt signal transduction pathway has been identified as an important mediator VEGF signaling downstream of Flk1 [14]

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