Antidepressant drugs as a complementary therapeutic strategy in cancer

Review

BDNF and VEGF in the pathogenesis

of stress-induced affective diseases:

An insight from experimental studies

Marta Nowacka, Ewa Obuchowicz

Department of Pharmacology, Medical University of Silesia, Medyków 18, PL 40-752 Katowice, Poland

Correspondence: Ewa Obuchowicz, e-mail: [email protected]

Abstract:

Stress is known to play an important role in etiology, development and progression of affective diseases. Especially, chronic stress, by

initiating changes in the hypothalamic-pituitary-adrenal axis (HPA), neurotransmission and the immune system, acts as a trigger for af-

fective diseases. It has been reported that the rise in the concentration of pro-inflammatory cytokines and persistent up-regulation of

glucocorticoid expression in the brain and periphery increases the excitotoxic effect on CA3 pyramidal neurons in the hippocampus re-

sulting in dendritic atrophy, apoptosis of neurons and possibly inhibition of neurogenesis in adult brain. Stress was observed to disrupt

neuroplasticity in the brain, and growing evidence demonstrates its role in the pathomechanism of affective disorders.

Experimental studies indicate that a well-known brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor

(VEGF) which have recently focused increasing attention of neuroscientists, promote cell survival, positively modulate neuroplas-

ticity and hippocampal neurogenesis. In this paper, we review the alterations in BDNF and VEGF pathways induced by chronic and

acute stress, and their relationships with HPA axis activity. Moreover, behavioral effects evoked in rodents by both above-mentioned

factors and the effects consequent to their deficit are presented. Biochemical as well as behavioral findings suggest that BDNF and

VEGF play an important role as components of cascade of changes in the pathomechanism of stress-induced affective diseases. Fur-

ther studies on the mechanisms regulating their expression in stress conditions are needed to better understand the significance of

trophic hypothesis of stress-induced affective diseases.

Key words:

BDNF, VEGF, animal models of stress, affective diseases

Abbrevations: ACTH – adrenocorticotropic hormone, BDNF

– brain-derived neurotrophic factor, CMS – chronic mild

stress, CNS – central nervous system, CREB – cyclic AMP re-

sponse element binding protein, CRH – corticotropin-releasing

hormone, ERK – extracellular sigal-regulated kinase, Flt-1 –

fms-like-tyrosine kinase, Flk-1 – fetal liver kinase, FRL –

Flinders Resistant Line, FSL – Flinders Sensitive Line, GR –

glucocorticoid receptor, L-HPA – limbic-hypothalamus-

pituitary-adrenal, MAPK – mitogen-activated protein kinase,

MR – mineralocorticoid receptor, NMDA – N-methyl-D-

aspartic acid, NGF – nerve growth factor, PI3K – phospha-

tidylinositol-3-kinase, PLCg – phospholipase C-g, TrkB – tro-

pomyosin receptor kinase, VEGF – vascular endothelial

growth factor

Introduction

Experimental studies and clinical observations have

indicated that stress plays a significant role in the

pathogenesis of mental disorders. Stress not only in-

fluences neurotransmission in the central nervous sys-

tem (CNS) but also leads to permanent changes in its

structure due to the activation of an array of neuroen-

docrine and immunological mechanisms [53]. Over-

activation of these systems elicits sensitization to

stressful stimuli, which promotes development of

Pharmacological Reports, 2013, 65, 535�546 535

Pharmacological Reports2013, 65, 535�546ISSN 1734-1140

Copyright © 2013by Institute of PharmacologyPolish Academy of Sciences

mental disorders [10]. It has been found that both

acute and chronic stress, as a modulator of central

nervous system function, in combination with genetic

background, often predisposes patients to develop-

ment of mental disorders and in later life can be a fac-

tor that triggers or aggravates disease episodes [9].

It appears that trophic factors play an important

role among agents implicated in the pathogenesis of

mental disorders [23]. Among members of the neuro-

trophin family, brain-derived neurotrophic factor

(BDNF) belongs to the most intensively studied. The

other neurotrophic factor, vascular endothelial growth

factor (VEGF) has recently become a focus of interest

in the context of mental diseases. BDNF plays a key

role in neurogenesis, promotes synaptic plasticity and

neuronal cell survival while its reduced expression

can contribute to structural anomalies and functional

impairment in the central nervous system. VEGF also

participates in the mentioned processes. In the light of

these findings, it can be expected that low levels of

trophic factors, in particular BDNF, can be engaged in

etiology of mental disorders [27, 100].

Implication of stress axis mechanisms

in the development of affective disorders

It has been demonstrated that there is a clear relation-

ship between disturbances induced by, especially

long-lasting, stressful stimuli and mental disorders.

Different stress factors (mental, environmental, so-

cial) increase the risk of central nervous system dis-

eases, including affective and anxiety disorders [69]

(Fig. 1). Reactions to stress are regulated by the

limbic-hypothalamic-pituitary-adrenal axis (L-HPA)

together with locus coeruleus, the activity of which

influences adrenergic system tone. Corticoliberin

(CRH, corticotropin-releasing hormone) released

from the hypothalamus increases synthesis and re-

lease of adrenocorticotropic hormone (ACTH) from

the anterior lobe of the pituitary gland, and activates

adrenergic system by directly affecting its neurons.

ACTH stimulates adrenal cortex and medulla to ele-

vated release of cortisol (corticosterone in rodents)

and catecholamines, respectively. Catecholamines

and glucocorticosteroids, the main stress mediators,

initiate intracellular adaptive changes in the whole or-

ganism [4, 36].

The limbic structures: the hippocampus, amygdala

and middle frontal cortex influence HPA axis activity

in response to stress by sending neuronal connections

to the hypothalamus [42]. When the system is bal-

anced, the stress axis is regulated by feedback mecha-

nisms. Cortisol/corticosterone, acting via steroid re-

ceptors, inhibit production and secretion of hormones

in brain structures. Mineralocorticoid receptors (MR)

occur in the limbic structures while glucocorticoid re-

ceptors (GR) are distributed all over the brain. GR ex-

pression is particularly high in regions engaged in the

mechanism of stress response, like the pituitary gland,

hypothalamus, amygdala and hippocampus. The men-

tioned receptors play various roles in stress response.

MR stimulation results in tonic inhibition of CRH

synthesis and release in the hypothalamus while GR

mediates the response to high doses of glucocorticos-

teroids participating in abatement of stress reaction. It

is known that incorrect GR function leads to dysregu-

lation of the L-HPA axis [22, 43]. However, data from

experiments on animal models of chronic and acute

stress indicate a decrease [42], increase [62] and no

changes [63] in GR expression in the hippocampus.

Long-term stress distorts negative feedback mecha-

nisms which cease to function properly that causes the in-

536 Pharmacological Reports, 2013, 65, 535�546

Hippocampal

Fig. 1. Schematic representation of the elements involved in thepathogenesis of stress-induced affective diseases

creased release of both CRH and glucocorticosteroids

thus further damaging neurons, particularly in the

CA3 region of the hippocampus [26, 98]. It seems that

only at the initial stage of hyperactivation of neuro-

transmitter systems glucocorticosteroids have protec-

tive effect on hippocampal neurons helping preserve

the balanced response to changing environment [60].

Both the consequences of glucocorticosteroid-induced

changes in the stress axis, activation of neurotransmitter

systems [42] and altered activity of the immune system

[21] play a role in the pathomechanism of mental disor-

ders. The majority of depressed patients show, apart from

hypercortisolemia, the impairment of dexamethasone-

induced inhibition of endogenous cortisol release which

indicates lowering of glucocorticosteroid receptor sensi-

tivity [70]. The increased weight of the adrenal glands

visible in radiographic studies suggests a prolonged and

excessive trophic effect of ACTH on these gland [65].

Depressive syndromes were found to be associated

with hyperactivity of the L-HPA axis, an weakened

feedback inhibition of this axis and in some patients,

with hyperactivity of the adrenergic system [69]. Corti-

costerone treatment or exposure to stressful stimuli were

observed to decrease serotonin (5-HT) level in the brain

and to diminish density of serotonergic 5-HT1A recep-

tors. The impairment of 5-HT transmission, like nor-

adrenergic system failure, can diminish production of

neurotrophic factors due to unfavorable changes in the

second messenger systems in the cell [103].

Stress modulates activity of the immune system. Pro-

inflammatory cytokines released by the immune cells

stimulate L-HPA axis. IL-1 and IL-6 promote CRH re-

lease from the hypothalamus and directly increase ACTH

secretion from the pituitary gland [79, 101]. Moreover,

exposure to stressful events (e.g., open field) increased

pro-inflammatory cytokine release prior to surge of glu-

cocorticosteroids, which suggests that elevated concentra-

tions of these hormones can have protective effect on the

CNS neurons, also in the case of damage produced by the

immune system hyperactivation [19, 102].

Stress-induced morphological changes

in the hippocampus as a consequence

of disordered synaptic plasticity

and neurogenesis

Synaptic plasticity is defined as the ability of the brain

to adapt to environmental changes. Its impairment by,

for instance, a prolonged stress, can provoke morpho-

logical changes in brain structures and functional

deficits of many molecular and cellular mechanisms

[71]. Distortion of neuronal plasticity results mainly

from suppression of neurogenesis, cell atrophy or en-

hanced apoptosis [17].

The hippocampus is the structure which is the main

target of pathogenesis and treatment of affective diseases.

This brain structure is engaged in learning and memory

processes which, at the cellular level, depend on the

modulation of neuronal plasticity [98]. It is believed that

neurogenesis, progressing also in adults, is crucially in-

volved in learning and memory processes. Neurogenesis

occurs mostly in the subgranular zone of the dentate gy-

rus of the hippocampus. Neurogenesis in the adult brain is

a dynamic process of creation, maturation, migration and

integration of new neurons. This process can be up- or

down-regulated by various neuroendocrine, environ-

mental or pharmacological factors [40, 71]. Disruption of

neurogenesis is aggravated by chronic stress, increased

glucocorticoseroid level or advanced age [26].

It is supposed that newly created neurons partici-

pate in the regulation of the changes in the hippocam-

pus induced by anxiety and stress and that they can

prevent development of depression and mediate ac-

tion of antidepressant drugs [24, 78]. According to the

hypothesis referred to as “trophic hypothesis”, stress

disturbs the formation of new neurons, which leads to

hippocampal damage and disease progression while

the action of antidepressant drugs largely consists in

restoration of the proper level of neurogenesis [39].

Stress suppresses hippocampal granular cell prolif-

eration and reduces the number and length of apical

dendrites of pyramidal neurons in the CA3 region,

which are particularly vulnerable to stressful stimuli

[25]. Studies conducted in experimental animal mod-

els demonstrated atrophy and death of pyramidal cells

in the CA3 region of the hippocampus as the result of

exposure to prolonged stress [26, 60]. Similar effect

was noted after glucocorticosteroid treatment at doses

producing similar brain level of these hormones as in

stressful situations [38]. These processes can be

blocked by prior administration of an NMDA (N-me-

thyl-D-aspartic acid) receptor antagonist which sug-

gests the involvement of the enhanced glutamatergic

transmission in the mechanism of destructive action

of stress and glucocorticosteroids on neuronal groups

and neurogenesis [37]. Moreover, exposure to stress

or glucocorticosteroids increases sensitivity of py-

ramidal cells of the CA3 region to such damaging fac-

tors as hypoglycemia or hypoxia [79, 80].

Pharmacological Reports, 2013, 65, 535�546 537

BDNF and VEGF in stress-induced affective diseasesMarta Nowacka and Ewa Obuchowicz

Brain imaging studies in depressed patients demon-

strated a smaller hippocampal volume and altered

shape [11, 55, 77]. At present, two causes have been

proposed to explain these changes: 1) postmortem

studies showed an increased packing density of neu-

ronal and glial cells with concomitant reduction of

neuron soma size in pyramidal regions and the dentate

gyrus of the hippocampus [89] and 2) the hippocam-

pal shrinkage and impairment of its function resulting

in the weaker inhibition of endocrine activity of the

HPA axis can be the result of the suppressed dentate

gyrus cell proliferation or their diminished survival

[47]. Nuclear magnetic resonance volumetric studies

in healthy subjects with familial history of depressive

disorders evidenced a smaller volume of the hippo-

campus, which suggests that genetic factors can con-

tribute to the observed structural changes [15].

Since a positive correlation was shown between the

hippocampus shrinkage and the cognitive deficits and

memory disturbances in depressed patients, it is be-

lieved that these disturbances are a functional conse-

quence of the structural changes in this structure [98].

The effect of stress on brain-derived

neurotrophic factor (BDNF)

Neurotrophic factors (neurotrophins) are a group of

proteins possessing similar structure, synthesized in

peripheral tissues innervated by sensory and sympa-

thetic neurons and in neurons of some brain structures

[7]. The greatest role in the pathogenesis of affective

disorders has been attributed to BDNF (Figs. 1, 2).

This factor influences neurons of both central and pe-

ripheral nervous system. During embryonic develop-

ment BDNF induces cell differentiation and deter-

mines neuronal survival. In the nervous system of

adult organisms, BDNF participates in the regulation

of cell survival and maintaining of their physiological

activity [58, 93]. It affects development of serotoner-

gic, dopaminergic, noradrenergic and cholinergic neu-

rons [2, 28]. This neurotrophin diminishes neuronal

degeneration, and induces and enhances synaptic

plasticity (for instance, influencing long-term poten-

tiation) [58]. The exposure to damaging factors, like

hypoxia, ischemia or neurotoxic substances, initially

increases BDNF expression and its neuroprotective

action [8].

The highest level of BDNF expression was ob-

served in the limbic structures: the hippocampus,

amygdala and prefrontal cortex [92], where its bio-

logical effect is mediated by an interaction with spe-

cific transmembrane tyrosine kinase (TrkB) receptor.

After BDNF binding, Trk receptors undergo auto-

phosphorylation, and the produced phosphotyrosine

becomes a binding site for proteins initiating one of

three main intracellular signal cascades: mitogen-

activated protein kinase (MAPK), phosphatidylinosi-

tol-3-kinase (PI3K) or phospholipase C-g (PLCg)

pathways. BDNF gene transcription in the above-

mentioned brain structures is regulated by the tran-

scription factor, cyclic AMP response element bind-

ing protein (CREB) [46, 92].

In the context of studies confirming the changes in

the limbic structures (mostly the hippocampus),

which are engaged in the pathogenesis of mental dis-

orders, and an undoubted role of stress in their

pathomechanism, it was important to look for an an-

swer to the question about the effect of chronic stress

on BDNF expression (Figs. 1, 2).

The studies on animal models demonstrate the

stress-induced dysregulation of BDNF expression.

The first studies in this field were presented by Smith

et al. [88] in 1995. They showed a significant de-

crease in BDNF expression in the dentate gyrus of the

538 Pharmacological Reports, 2013, 65, 535�546

Fig. 2. Influence of BDNF and VEGF activity on the effects depend-ent on the hippocampal function

hippocampus in rats exposed to chronic immobiliza-

tion stress. This result was confirmed by later studies

[94, 96]. The studies on chronic stress models utiliz-

ing different kinds of stressors, like foot shocks [73],

maternal separation [75], documented a lower expres-

sion of BDNF in the dentate gyrus of the hippocam-

pus. Similarly, the reduced BDNF mRNA levels were

found in the hippocampus but not in the frontal cortex

of rats exposed to chronic unpredictable stressors

[18]. The decreased BDNF expression was noted in

the hippocampal regions showing the greatest stress-

induced changes, namely in the CA3 pyramidal cells

responding to stress with atrophy of dendrites, and in

the subgranular zone of the dentate gyrus reacting

with lower neurogenesis [23]. In the social isolation

stress model in mice, BDNF was reduced not only in

the hippocampus but also in the cortical and subcorti-

cal regions [72]. Moreover, the decrease in BDNF ex-

pression correlated with behavioral changes character-

istic of depression, which were observed in the learned

helplessness model. On the other hand, Allaman et al.

[1] observed no changes in BNDF expression in the

amygdala and hippocampus after exposure of rats to

chronic mild stress (CMS) procedure. It could be

caused by the use of too weak stressors, which did not

produce any changes in BDNF expression.

The changes in concentration of BDNF and other

neurotrophins were also revealed in genetic models of

depression. The decrease in BDNF and nerve growth

factor (NGF) concentrations in the frontal and occipital

cortices and the hypothalamus were noted in Flinders

Sensitive Line (FSL) of rats compared to the control

group – Flinders Resistant Line (FRL). Exposure of

FSL rats to chronic mild stress induced depression-like

symptoms, like anhedonia and lower body weight gain.

Greater BDNF and NGF decreases were reported in

FSL females compared to males which suggests

gender-related susceptibility to depression [3].

Genetic studies investigating the effect of stress on

BDNF were mostly focused on functional Val66Met

gene polymorphism which is the cause of a lowered

synthesis and release of this neurotrophin [30, 35].

The relationship between the Met allele and the

changes in neuronal structure was confirmed in ani-

mal models. The Met allele-synthesizing mice

showed a lower number and length of apical dendrites

in the hippocampus [52] and prefrontal cortex [54],

which resembles structural changes observed after ex-

posure to stress. However, in male mice, this func-

tional deletion in BDNF gene in the forebrain was not

sufficient for manifestation of depression-like behav-

iors. In contrast, in females of these mice, depression-

like behaviors were enhanced which confirms earlier

suggestions derived from clinical observations that

susceptibility to depression is sex-related. Epidemio-

logical studies have indicated that women are more

susceptible to affective disorders than men [48, 61,

97]. It was observed that the blockade or reduction of

BDNF expression increased susceptibility to stress.

The blockade of BDNF expression in experimental

models led to reduced neurogenesis in some brain re-

gions and to escalation of depression-like behaviors.

“Antidepressant” action of this neurotrophin has been

documented [44, 87, 90, 91]. Chronic administration

of recombinant BDNF to the midbrain induced sig-

nificant changes in behavioral tests: the learned help-

lessness test and forced swim test in comparison with

the control neurotrophin-naive group [90]. Further-

more, a single intrahippocampal BDNF injection in

rats increased the number of newly formed neurons

[82] while chronic peripheral administration of this

neurotrophin to mice elevated neuronal survival in the

dentate gyrus of the hippocampus [83].

The hippocampal BDNF mRNA level showed

a negative correlation with plasma glucocorticosteroid

level. The decrease in BDNF mRNA in the rat hippo-

campus after repeated intraperitoneal administration of

corticosteroids, mimicking chronic stress, is well docu-

mented [14, 84]. Diminution of BDNF expression after

chronic corticosterone administration is not limited to

the hippocampus but extends also to some areas of the

frontal cortex [29]. Atrophy of the limbic structures af-

ter chronic administration of glucocorticosteroids is

probably due to the lowered BDNF expression [68].

These results were not confirmed by Chiba et al. [16],

who found no changes in BDNF concentration, meas-

ured by western blot analysis, with a concomitant con-

spicuous decrease in glucocorticoid receptor expres-

sion in the prefrontal cortex of rats exposed to chronic

immobilization stress. However, they noted the at-

tenuation of BDNF-induced glutamate release from

prefrontal cortex slices from the stressed rats. In con-

trary to the others, whose papers are mentioned above,

Chiba et al. evaluated only the BDNF concentration

but not BDNF expression. It is known that changes in

mRNA levels are not always reflected at the protein

level because gene expression is controlled at different

stages and in different ways.

In adrenalectomized rats, which lacked endoge-

nous corticosterone, the hippocampal BDNF expres-

Pharmacological Reports, 2013, 65, 535�546 539

BDNF and VEGF in stress-induced affective diseasesMarta Nowacka and Ewa Obuchowicz

sion increased. Treatment of these rats with dexa-

methasone normalized BDNF mRNA level to the

control level [14]. These studies have proven that

BDNF expression is regulated by glucocorticoster-

oids, among other factors.

Changes in BDNF expression, stress and glucocorti-

costeroids influence regulation of long-term potentiation

in the hippocampus. The drop in BDNF expression in

the rat hippocampus after stress exposure was positively

correlated with disruption of spatial and visual memory

which was evidenced in behavioral tests: the elevated

Y-maze test and novel object recognition test [51].

TrkB receptor is an important component of stress

response of the organism at the cellular level. The in-

crease in TrkB mRNA level accompanied by a de-

crease in BDNF gene expression and protein level

was observed in the repeated immobilization stress

model [66] or in the forced swim test [86]. In addi-

tion, Shi et al. [86] investigated the effect of chronic

mild stress induced by forced swimming on BDNF

expression and protein level, and TrkB expression in

young (2 months old) and old (22 months old) rats.

BDNF expression and protein level were significantly

decreased in old rats and the decrease persisted for

12 h after stress exposure. These results suggest that

both stress and aging process influence the regulation

of expression of BDNF and its receptor. In opposite to

the lowered BDNF mRNA level in stress-exposed

rats, the TrkB expression was increased. In the

authors’ opinion, the observed up-regulation of TrkB

mRNA expression was probably due to a compensa-

tive adaptation to repeated stressful stimulation [86].

The modulation of TrkB expression can also contrib-

ute to sensitization of hippocampal neurons to low

BDNF concentrations induced by chronic stress [81].

It should be noted that the data on BDNF dysregu-

lation in acute stress models were sometimes different

from those obtained after chronic stress exposure. Ni-

buya et al. [66] observed the increased expression of

this neurotrophin in the dentate gyrus and CA3 region

of the hippocampus and in the hypothalamus after ex-

posure to a single episode of 60 min immobilization

stress. A considerable increase in BDNF expression

and its protein level was seen in the hippocampus of

rats exposed to short-lasting sleep disturbances or

subjected to a single procedure of forced swimming in

cold water [86]. On the other hand, Scaccionoce et al.

[81] and Murakami et al. [62] reported that both

chronic and acute stress reduced BDNF expression in

the rat hippocampus. Moreover, Murakami et al. [62]

observed a stronger drop in BDNF expression in the

CA3 region and dentate gyrus of the hippocampus in

rats in response to acute stress in comparison with

chronic stress. The weaker decrease in BDNF expres-

sion in the rat hippocampus in response to chronic

stress could be caused by elevated plasma concentra-

tion of glucocorticosteroids and greater GR immuno-

reactivity in the dentate gyrus of the hippocampus

what were not observed in the effect of acute stress.

These results confirmed earlier observations that hip-

pocampal BDNF expression was negatively corre-

lated with plasma glucocorticosteroid concentration.

According to Scaccianoce et al. [81], the decrease

in hippocampal BDNF expression in the rats exposed

to chronic foot shock was accompanied by the in-

creased plasma corticosterone level. BDNF expres-

sion was higher in the rats that learned to avoid

a stressful stimulus, despite high plasma corticoster-

one concentrations than in the stressed group.

It should be remembered that BDNF expression

can vary in different regions of the CNS. For instance,

exposure to chronic social defeat stress increased

BDNF expression in the nucleus accumbens of the

mesolimbic system [6].

Although chronic stress is thought to be more detri-

mental, but a single exposure to a strong stressful

stimulus also changes functioning of the central

monoaminergic routes, L-HPA axis and immune sys-

tem. Acute stress triggers short-term protective mecha-

nisms. It is believed that the increase in BDNF mRNA

expression and protein level is a factor that directly or

indirectly participates in neuroprotective mechanisms.

On the other hand, chronic stress can lead to excessive

stimulation and functional distortion of neuroendocrine

systems that can reduce BDNF expression [63, 69, 71].

The effect of stress on vascular

endothelial growth factor (VEGF)

Activities of vascular endothelial growth factor

(VEGF) in the CNS spark increasing interest among

researchers. In recent years, neurotrophic and neuro-

protective properties of VEGF brought new hopes due

to its trophic effect on neurons and glia cells [34, 67].

VEGF belongs to signal proteins involved in the

regulation of physiological and pathological angio-

genesis [33]. It is synthesized by many cells, like en-

540 Pharmacological Reports, 2013, 65, 535�546

dothelial cells, macrophages, lymphocytes T, smooth

muscle cells, nephrocytes, keratocytes, osteoblasts,

cancer cells, brain cells: astrocytes, neuronal stem

cells. VEGF stimulates proliferation and survival of

endothelial cells and acts as an NO-dependent vasore-

laxant. It influences formation of vascular networks

and increases vascular permeability [13, 20, 32]. In the

brain, VEGF participates in vasculogenesis and angio-

genesis in embryonic life and postnatal period [12].

VEGF acts by binding with specific tyrosine kinase

receptors: VEGFR1 (Flt-1, fms-like-tyrosine kinase)

and VEGFR2 (Flk-1, fetal liver kinase). VEGF inter-

action with the extracellular domain of VEGFR2 trig-

gers phosphorylation of tyrosine residues in the tyro-

sine kinase domain [12, 74]. In neurons and Schwann

cells, VEGFR2 stimulation activates PLCg/MAPK

pathway. In astrocytes and microglia, VEGF activates

MAPK/ERK (ERK, extracellular sigal-regulated ki-

nase) by stimulation of VEGFR2, and PI3K by inter-

action with VEGFR1 [12].

In the brain, apart from the effects on nervous cell

metabolism, VEGF directly stimulates neurogenesis

(Fig. 2). This effect was observed both in in vitro and

in vivo studies [49, 57, 64]. Hippocampal neurogene-

sis regulated by VEGF is stimulated by environmental

enrichment and exercises, learning and antidepressant

drugs, while stress and aging diminishes it. Suppres-

sion of neurogenesis in rats by irradiation causes fear

and depression-like behaviors [31, 99]. In addition,

VEGF activates neurogenesis by stimulating endothe-

lial cells to release neurotrophic factors, e.g., BDNF,

which improves neuronal survival and integration in

the subventricular zone of the dentate gyrus of the

hippocampus. Intracerebral administration of VEGF

stimulated neurogenesis in the subventricular and

subgranular zone of the dentate gyrus of the hippo-

campus [76, 85]. Research results suggest that VEGF

influences neuronal plasticity in the CNS of adult ani-

mals but the mechanism of this action has not been

elucidated so far. It is supposed that VEGF by its neu-

roprotective activity, like BDNF, promotes the hippo-

campus-dependent processes, like learning and mem-

ory [56, 59].

As mentioned above, synaptic plasticity, which is

important for the formation of memory traces, learn-

ing, and neurogenesis in the adult brain, play a signifi-

cant role both in stress response and repeated stress-

induced adaptations. The mechanism responsible for

the relationship between the stress-induced distortion

of synaptic plasticity and suppression of neurogene-

sis, and the depressive behavior has not been fully

elucidated so far. It appears that due to the involve-

ment of VEGF in synaptic plasticity and neurogene-

sis, this factor can be engaged in etiopathogenesis of

mental disorders induced by stress.

The effect of stress on VEGF gene expression and

protein level was investigated in several studies.

VEGF expression in the CA3 region of the hippocam-

pus was studied using an in situ hybridization method

in stress-sensitive and stress-resistant rats. The study

showed that VEGF mRNA level was decreased in the

stress-sensitive group exposed to CMS procedure

compared to the stress-resistant group. The authors

suggested that VEGF down-regulation in the CMS-

sensitive rats could contribute to functional hippo-

campal damage due to a weaker neuroprotective ac-

tion of this factor [5].

Heine et al. [41] demonstrated the down-regulation

of VEGF and its receptor VEGFR2 in the dentate gy-

rus of the hippocampus of rats exposed to chronic

stress procedure lasting 21 days. These rats were ex-

posed to such stressors as immobilization, forced

swimming in cold water, and intermittent social isola-

tion and group housing. The changes in the hippo-

campal VEGF and VEGFR2 expression were investi-

gated using immunocytochemical methods. A smaller

VEGF immunoreactivity compared to the control

group was observed in cytoplasm of astrocytes in the

hilus of the hippocampus and in the granular cell

layer. In stressed rats, VEGFR2 expression was also

lowered in the dentate gyrus and the hilus of the hip-

pocampus. That experiment was performed on the

group of stressed and control unstressed rats and on

the group of rats which were maintained under stan-

dard conditions for 3 weeks following the stress pro-

cedure in order to observe regenerative mechanisms.

In the last group, VEGF and VEGFR2 expression

in the brain regions under study was increased com-

pared to the stress-exposed group. The results of those

studies confirmed the hypothesis that vascularization

is an important component aiding neurogenesis, and

susceptible to a prolonged stress. Chronic stress-in-

duced suppression of hippocampal neurogenesis was

seen mostly in the region vascularized by capillaries.

According to the authors’ opinion, this led to reduc-

tion of blood flow and density of capillaries in the

hippocampus, which resemble vascular disturbances

observed often in depressed patients.

However, further experiments of Bergström et al.

[5] did not show significant differences in VEGF ex-

Pharmacological Reports, 2013, 65, 535�546 541

BDNF and VEGF in stress-induced affective diseasesMarta Nowacka and Ewa Obuchowicz

pression in the CA3 region of the hippocampus be-

tween rats exposed to acute and chronic immobiliza-

tion stress (lasting 1 h and applied once or daily for

a week) and unstressed animals.

The newest studies focusing on the effect of stress

and exercise on VEGF expression, vascular density

and neurogenesis in the hippocampus were conducted

in the chronic unpredictable stress model. Mice were

exposed to such stressors as immobilization, low tem-

perature (4°C), water and food deprivation in the

night, nocturnal light exposure, forced swimming for

15 min and cage rotation. No differences in the hippo-

campal and plasma VEGF concentration were seen

between stressed and unstressed groups. However,

chronic stress induced transient depression-like be-

haviors of mice, and, like in the latter paper, de-

creased vascular density and neurogenesis in the hip-

pocampus. Regular exercise reversed these disadvan-

tageous physiological and behavioral changes but had

no effect on the hippocampal and plasma VEGF ex-

pression in mice [50].

Uysal et al. [95] evaluated the effect of acute foot

shock stress on the hippocampal VEGF concentration

in young female and male rats. Moreover, in order to

examine the effect of acute stress on spatial memory,

behavior of rats was evaluated in the Morris water

maze test. They evidenced that both female and male

rats exposed to foot shocks (of low and high intensity)

showed a higher VEGF expression, improved learning

ability and better spatial memory compared to the con-

trol group. These results suggest that VEGF is directly

implicated in improvement of cognitive functions in

rats. VEGF concentration in females was much lower

than in males, which confirms the earlier observations

that sensitivity to stress is sex-dependent.

It is known that VEGF action on neuroplasticity

and neurogenesis is mediated by VEGFR2 and that

exposure to a prolonged stress or exogenous gluco-

corticosteroids induces neurochemical and behavioral

disruption in rodents [45]. Howell et al. [45] demon-

strated an inhibitory effect of chronic corticosterone

on VEGFR2 expression in the frontal cortex of mice.

They documented a significant decrease in VEGFR2

protein level, as demonstrated by western blot analy-

sis, in the frontal cortex of mice which were treated

with corticosterone for 7 weeks, vs. the control group.

The plasma level of this protein in the stressed group

was also diminished. In contrast, the frontal cortex

and plasma VEGF protein level in the corticosterone-

treated rats was elevated compared to the control

group. These researchers observed GR down-regu-

lation which underlined significance of these recep-

tors for the suppression of VEGFR2 expression in-

duced by chronic corticosterone administration. These

results suggest that VEGF synthesis in the frontal cor-

tex is increased by a feedback mechanism in response

to the inhibition of this signal route, mediated by

VEGFR2 both in the brain and periphery. However, it

cannot be excluded that the increase in the central

VEGF concentration is a response to the lowered pe-

ripheral VEGF level induced by chronic corticoster-

one administration.

Conclusions

Long-term or intense stress, which is considered to be

a significant factor in the pathogenesis of affective

disorders, produces adverse effects on brain structures

leading to their permanent changes [26]. This effect is

largely dependent on excessive activation of the

L-HPA axis and impairment of its crucial regulatory

feedback mechanism. In addition, stress exposure dis-

rupts neuronal plasticity which can result from sup-

pressed neurogenesis, cell atrophy or enhanced apop-

tosis [17, 26]. Although the contribution of the dimin-

ished neurogenesis to the pathomechanism of stress-

induced affective disorders seems probable, its sig-

nificance has not been fully explained, yet. It is diffi-

cult to unequivocally resolve to what extent the re-

duced neurogenesis influences morphological changes

observed in the brains of patients and whether indeed

it promotes development of affective disorders. How-

ever, it does not appear that diminution of the number

of newly formed neurons could be the trigger initiat-

ing the cascade of the observed functional changes in

neuronal networks. Instead, it rather seems that distur-

bances of synaptic plasticity also of other origin than

limited neurogenesis can play a more important role.

Heterogeneity of affective disorders suggests that

they can be caused by different functional anomalies

in neuronal networks underlain by a number of

mechanisms.

BDNF and VEGF are crucially involved in the pro-

cesses of neurogenesis and synaptic plasticity. These

factors are sensitive to stressors, which was con-

firmed by results of the studies on animal models of

542 Pharmacological Reports, 2013, 65, 535�546

stress induced by immobilization, foot shocks, forced

swimming, social isolation, etc., which evidenced

dysregulation of these factors. Moreover, BDNF

alone showed “antidepressant” effect, and a single in-

tracerebral BDNF administration, and VEGF alike,

stimulated neurogenesis in vivo. On the other hand,

stress-induced suppression of BDNF and VEGF ex-

pression evokes in animals behaviors characteristic of

depression which are reversed by antidepressant

drugs or exercise and environmental enrichment that

increase expression of these factors. It was demon-

strated that after stress exposure, BDNF and VEGF

were directly affected by: (i) elevated levels of gluco-

corticosteroids, which produced a stronger effect un-

der stress conditions due to GR dysfunction, (ii) in-

creased activity of monoaminergic systems or (iii) other

detrimental factors, like glutamate. Other significant

factors influencing different BDNF and VEGF ex-

pression in response to stress include sex an age. Old

male and female rats alike showed lower BDNF and

VEGF expression after exposure to stress compared

to young males and females. Thus, the results of a ma-

jority of experimental studies have indicated the im-

plication of BDNF and VEGF in the pathogenesis of

stress-induced affective disorders, which is the basis

for “the neurotrophic hypothesis” of the pathomecha-

nism of these disorders. Of course, this hypothesis

does not abolish “the monoaminergic hypothesis” but

supplements it.

It is difficult to resolve to what extent the stress-

induced reduction in BDNF and VEGF expression di-

rectly contributes to the distortions of synaptic plas-

ticity and neurogenesis in the hippocampus but it is

supposed that structural and morphological changes

in this structure in the patients suffering from affec-

tive disorders are at least partially consequent to the

decreased expression of these factors. Since it is not

known whether these changes are the effect of the dis-

ease or its cause, it is difficult to assess the sequence

of changes, i.e., whether dysregulation of BDNF and

VEGF expression precedes or coincides with the

changes in the hippocampus. The results of a few

studies showing a paradoxical increase in BDNF and

VEGF expression following stress exposure in the

brain of rodents can indicate that other pathways can

also be engaged in the pathogenesis of stress-induced

diseases. However, based on the majority of studies

conducted so far and reviewed in this article, it ap-

pears that BDNF and VEGF fulfill an important but

not a key role in the pathogenesis of these diseases,

and full elucidation of the mechanisms regulating

their expression will contribute to answering still un-

answered questions about the pathomechanism of af-

fective disorders.

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Received: September 25, 2012; in the revised form:December 14, 2012;accepted: January 8, 2013.

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