Neuropeptides
Volume 46, Issue 1 , Pages 1-10, February 2012

Vascular endothelial growth factor (VEGF) and its role in the central nervous system: A new element in the neurotrophic hypothesis of antidepressant drug action

Department of Pharmacology, Medical University of Silesia, Medykow 18 Street, 40-752 Katowice, Poland

Received 7 March 2011; accepted 20 May 2011. published online 30 June 2011.

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Abstract 

Vascular endothelial growth factor (VEGF) is a well-known cellular mitogen, and a vascular growth factor and permeability regulator. It participates in physiological and pathological processes of angiogenesis and in the development of lymphatic vessels. In addition to the proangiogenic activity, studies of recent years have revealed neurotrophic and neuroprotective potential of VEGF both in the peripheral and central nervous system. VEGF directly influences Schwann cells, neuronal progenitor cells, astrocytes and microglia. This factor plays an import role in developmental processes of the nervous tissue since it is implicated in neurogenesis and the regulation of neuronal development, and in the differentiation and formation of vessels in the brain. VEGF elicits its biological effect via an interaction with three VEGF receptor subtypes: VEGFR1, VEGFR2 and VEGFR3. In the nervous system, VEGFR2 signaling prevails. VEGF as a trophic factor, influencing both vascular endothelial cells and brain cells is a focus of the studies on neuropsychiatric disorders and psychotropic drug action. Antidepressant drugs were shown to induce hippocampal expression of VEGF. In addition, the experiments in animals models of depression have demonstrated that VEGFR2 signaling is indispensable for cellular and behavioral response to antidepressant drugs. Acquiring a deeper knowledge into the signaling pathways engaged in neurogenic and behavioral VEGF actions can unravel new targets for more efficient and quick acting antidepressant drugs.

Keywords: Vascular endothelial growth factor (VEGF), Signal transduction, Neurogenesis, Neuroprotection, Synaptic plasticity, Depression, Antidepressant drugs

 

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1. Introduction 

Vascular endothelial growth factor (VEGF) belongs to a group of signaling proteins involved in the regulation of physiological and pathological angiogenesis. This factor increases capillary vascular permeability and is also called Vascular Permeability Factor (VPF) or vasculotropin (Brochington et al., 2004, Carmeliet and Strokebaum, 2002, Folkman and D’Amore, 1996).

The vascular permeability factor was discovered by Senger et al. in 1983 whereas 6years later the respective gene was cloned and the protein endowed with mitogenic properties in endothelial cells was isolated by Ferrara and Davis-Smyth (1997) and was called vascular endothelial growth factor. Since then, numerous studies have documented that it is a key factor for both embryogenic and pathological angiogenesis (Ferrara and Davis-Smyth, 1997, Folkman and D’Amore, 1996). Physiological significance of VEGF was uncovered by experiments in VEGF knockout mice. Such embryos died on about 10th day of pregnancy, even when only one allele of the gene was knocked out. The Vascular Endothelial Growth Factor Receptor 1 or 2 (VEGFR1 or VEGFR2) knockout mice died even earlier between 8.5th and 9.5th day of embryonic development. That experiment initiated studies into proangiogenic action of VEGF (Robinson and Stringer, 2001).

In the last decade, central VEGF activity has been gaining increasing attention. Studies on the VEGF-induced angiogenesis during nervous tissue development and regenerative processes following cerebral ischemic damage are in progress. In recent years, promising results were obtained with respect to neurotrophic and neuroprotective potential of VEGF, which was discovered to be a neuronal and glial trophic factor (Brochington et al., 2004, Ruiz De Almodovar et al., 2009, Warner-Schmidt and Duman, 2007).

The most recent studies have focused on the implication of VEGF in antidepressant drug action. Antidepressants were shown in animal models to increase hippocampal VEGF expression which is important for behavioral responses induced by these drugs. It appears that VEGF action can rely on both the effect on vascular endothelium and on brain cells. For this reason, VEGF was suggested to be an important therapeutic target, particularly in depression accompanied by distorted cerebral blood flow (Warner-Schmidt and Duman, 2007, Warner-Schmidt and Duman, 2008).

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2. Regulation of VEGF expression 

VEGF (VEGF-A) is a heterodimeric glycoprotein with molecular weight from 34 to 64kDa, capable of heparin binding. Alternative posttranslational modifications of the VEGF protein in humans yield different VEGF-A isoforms containing 121, 145, 165, 189 and 206 amino acids (VEGF121, VEGF145, VEGF165, VEGF189, VEGF206). These proteins differ in biochemical and biological properties, like affinity for heparin, solubility, bioavailability and affinity for receptors (Azam et al., 2010, Cross et al., 2003, Cursiefen et al., 2004, Ferrara, 2009).

VEGF is synthesized by many cell types: endothelium, macrophages, activated platelets, lymphocytes T, smooth muscle cells, kidney cells, keratinocytes, osteoblasts, cancer cells and brain cells: astrocytes and neuronal stem cells. VEGF promotes proliferation and survival of endothelial cells and stimulates nitric oxide-dependent vasodilation. It influences vasculature formation and increases vascular permeability (Azam et al., 2010, Carmeliet and Strokebaum, 2002, Cross and Claesson-Welsh, 2001). In the brain, VEGF participates in angiogenesis both in embryonic and postnatal development (Carmeliet and Strokebaum, 2002). VEGF is a neuronal and glial trophic factor (Brochington et al., 2004).

VEGF expression is regulated by an array of mechanisms, among which hypoxia seems the most important. Hypoxia is one of crucial stimuli regulating expression of the genes involved in angiogenesis. Oxygen deficit in the cell induces synthesis of the transcription factor, hypoxia-inducible factor-1 (HIF-1), which activates VEGF gene promoter (Brochington et al., 2004, Harms et al., 2010). Cellular stress induced, for instance, by hypoglycemia, low pH, oxidative stress, may be another activator of VEGF expression (Zhang et al., 2000).

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3. VEGF receptors 

VEGF produces its effect via binding to specific tyrosine kinase receptors VEGFR1 (known as Fms-like-tyrosine kinase – Flt-1) and VEGFR2 (known as Fetal liver kinase – Flk-1 or kinase domain region – KDR) (Brochington et al., 2004, Quinn et al., 1993).

Although VEGF shows a greater affinity for VEGFR1 than for VEGFR2, the function of the latter is better known. VEGFR1 is thought to modulate the VEGFR2-mediated signaling. In addition, it can act as a decoy receptor/trap which limits VEGF binding to VEGFR2. The VEGFR1 signaling pathway is implicated in chemotaxis of monocytes/macrophages, mobilization of hematopoietic precursors, recruitment of endothelial progenitor cells, maturation of dendritic cells and in pathological angiogenesis (Brochington et al., 2004, Namiecińska et al., 2005, Olsson et al., 2006, Terman and Stoletov, 2001). This receptor participates in embryogenesis which was confirmed by the observation that fetuses of VEGFR1 knockout animals died due to vascular disorganization. VEGFR1 mediates neuroprotective action of VEGF under pathological circumstances (Ruiz De Almodovar et al., 2009, Sun and Guo, 1999). VEGFR1 was shown to occur also in a soluble form (sVEGFR1, sFlt-1). Its physiological role remains unknown but probably it binds VEGF in blood, thereby preventing endothelial cells from being stimulated (Cursiefen et al., 2004, Namiecińska et al., 2005, Olsson et al., 2006). VEGFR1 expression is regulated by hypoxia, and this process is mediated by HIF-1 (Yang et al., 2003).

VEGFR2 is the best characterized VEGF receptor. This receptor mediates almost all known cellular responses to VEGF including most of all elevation of vascular permeability, and mitogenic and angiogenic actions (Brochington et al., 2004, Robinson and Stringer, 2001, Terman and Stoletov, 2001). In the nervous system, VEGFR2 participates in the stimulating effect of VEGF on proliferation, migration and survival of nerve cells of different types, like microglia, astrocytes, neuronal stem cells, Schwann cells (Fig. 1). Human and mice plasma was shown to contain a soluble form of VEGFR2 (sVEGFR2, sFlk), which, like sVEGFR1, binds VEGF. Its concentration shows a negative correlation with tumor progression (Ruiz De Almodovar et al., 2009).

The VEGFR1, 2 and 3 receptors are accompanied by neuropilins 1 and 2 (NPR1, NPR2). Neuropilins are receptors for semaphorins which are axonal growth cone guidance molecules. They act as co-receptors and enhance VEGF signaling by increasing the VEGFR protein phosphorylation. Neuropilins are indispensable for neuronal signal transmission and for angiogenetic regulation. They are expressed in axonal terminals, vascular endothelial cells and in some cancer cells. They play an important role in the regulation of circulatory and nervous system development (Autiero et al., 2005, Cross et al., 2003, Neufeld et al., 1999, Ruiz De Almodovar et al., 2009).

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4. Intracellular VEGF signal transduction in endothelial and nerve cells 

There are many similarities in the intracellular signaling cascades induced by VEGF in endothelial cells and in neurons (Fig. 2). VEGF signal can be transduced into the cell after both ligand (VEGF) and receptor dimerization. VEGF interacts with an extracellular domain of the receptor which induces mutual phosphorylation of receptor subunits. Both receptors (VEGFR1, VEGFR2) are required for normal angiogenesis, although VEGFR2 signaling prevails in the nervous system (Brochington et al., 2004, Quinn et al., 1993, Yang et al., 2003).

VEGFR2 receptor activation induces phosphorylation of appropriate tyrosine molecules in the tyrosine kinase domain. The phosphorylated Tyr1175 binds phospholipase C-γ (PLCγ), which activates protein kinase C (PKC) by diacylglycerol (DAG) generation and by increasing the intracellular calcium ion concentration. Then, protein kinase C activates extracellular signal-regulated kinase 1/2 (ERK1/2) by Ras and Raf-1 proteins. This route participates in the activation of endothelial cell proliferation. In turn, activation of mitogen-activated protein kinase (MAPK) mediates the stimulation of endothelial cell migration (Brochington et al., 2004, Olsson et al., 2006, Zachary, 2003). It is known that focal adhesion kinase (FAK) and Src kinase family activation also enhances endothelial cell migration (Ruiz De Almodovar et al., 2009, Zachary, 2003).

Protein kinase C activation by VEGF via VEGFR2 stimulation produces an increased vascular permeability. This effect is indirectly dependent on NO which is generated from l-arginine by endothelial NO synthase (eNOS) (Ruiz De Almodovar et al., 2009).

The PI3K/Akt signaling pathway is important for endothelial cell survival. The Akt kinase activation elicits the inhibition of the proapoptotic protein Bad and caspase-9 and activates NFκB, which increases expression of prosurvival factors, like Bcl-2, Bcl-xL, c-IAP (Ruiz De Almodovar et al., 2009, Zachary, 2003).

Like in endothelial cells, VEGFR2 stimulation in neurons and Schwann cells activates PLCγ/MAPK pathways. In astrocytes and microglia cells, VEGF acting via VEGFR2, activates MAPK/ERK signaling pathways and acting via VEGFR1, stimulates PI3K pathway (Brochington et al., 2004, Ruiz De Almodovar et al., 2009). It has been demonstrated that the in vitro stimulating effect of VEGF on migration of neuronal precursors results from VEGFR2 stimulation which activates IQ motif containing GTPase activating protein (IQGAP1) (Ruiz De Almodovar et al., 2009).

VEGF protects nerve cells from apoptosis/necrosis. It promotes survival of neuronal precursors in the central nervous system. Molecular mechanisms by which VEGF regulates neuronal survival are not fully understood. It appears that it depends on PI3K/Akt and MAPK activation. These pathways also mediate VEGF-induced axonal growth (Brochington et al., 2004, Harms et al., 2010, Ruiz De Almodovar et al., 2009).

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5. Involvment of VEGF in the nervous system development 

There is a close embryogenetic parallelism between vascular and nervous system development. Both nervous system and circulation are composed of a network of afferent and efferent connections, like motor and sensory nerves in the nervous system and arteries and veins in the circulatory system. Both systems are regulated by similar cellular signals and cooperate with one another to coordinate growth and modeling of both networks: neuronal and vascular. Recent studies have demonstrated that similar molecular routes regulate cell differentiation and development of both systems. The processes of neurogenesis and angiogenesis are closely related to endothelial cell function. Molecules that control axonal growth (netrins, semaphorins, ephrins) regulate also vascular development. On the other hand, angiogenic molecules regulate neuron and axon formation. VEGF is an example of molecule that participates in neuronal and vascular cell development (Autiero et al., 2005, Eichmann et al., 2005, McCloskey et al., 2008, Nakamura et al., 2010, Ruiz De Almodovar et al., 2009).

It is believed that VEGF can be engaged in the nervous system development as a factor implicated in neurogenesis and in control of neuronal development on the one hand, and in differentiation and formation of vessels in the developing brain, on the other (Carmeliet and Strokebaum, 2002, Brochington et al., 2004).

VEGF and VEGFR2 receptor protein are synthesized by cortical neurons of 15-day-old mouse embryos (E15) in vitro and in vivo. VEGF promotes endothelial cell survival and angiogenesis by a paracrine action, and neuronal survival in the CNS by autocrine and paracrine routes. VEGFR2 is activated in cortical neurons and initiates signal transduction by a cascade containing PI3, Akt, adaptor proteins Shc, Nck and kinases ERK, p90RSK and STAT3. The MEK-ERK pathway is of a key significance for survival of cortical neurons in vitro (Ogunshola et al., 2002).

In higher organisms, VEGF is involved in vascularization of the neural tube, a precursor of the brain and the spinal cord. Recent reports have indicated that the neural tube vascularization develops by formation of the perineural vascular plexus (PNVP) enclosing the neural tube from which new vessels sprout. In tissue co-cultures of the neural tube with the mesoderm, an origin of endothelial cells, VEGF inhibitors suppressed the PNVP formation. During vessel “sprouting”, VEGF is synthesized in the neural tube by neuronal precursors occurring in the ventricular system and in motor neurons. Highly specific VEGF expression is dependent, among other factors, on the protein Sonic hedgehog. This protein is an angiogenic factor participating in vessel formation in the neural tube via the regulation of VEGF expression (Autiero et al., 2005, Ruiz De Almodovar et al., 2009).

Vascularization of certain regions of the brain is regulated by VEGF. For instance, VEGF expression was noted in Purkinje cells and in astrocytes during cerebellar development (McCloskey et al., 2005).

Brain cells and vessels influence development of one another. In developing retina, astrocytes grow outwardly thereby forming a template for growing vessels. At the beginning, the developing retina has no vessels and experiences hypoxia which stimulates an upregulation of astrocytic VEGF expression. An increased VEGF concentration promotes vessels growth. Tissue supply with oxygen by newly formed vessels produces downregulation of VEGF expression in astrocytes and their differentiation (Ruiz De Almodovar et al., 2009).

VEGF regulates nerve cell migration in the CNS. For instance, the migration of facial motor neurons in the developing mouse rhombencephalon is regulated by VEGF and NRP1 (Autiero et al., 2005, Ruiz De Almodovar et al., 2009).

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6. VEGF as a neurogenesis stimulating factor 

In the nervous system, VEGF regulates vascular growth and directly influences different types of brain cells: neuronal stem cells (NSC), neurons, microglia and astrocytes. Apart from the effects on the mentioned cells, VEGF stimulates neurogenesis in vitro and in vivo (Maurer et al., 2003, Namiecińska et al., 2005).

Neurogenesis proceeds in a majority of adult humans and animals. Development of new nerve cells in the brain of an adult person is a dynamic process, regulated by many factors. The hippocampal neurogenesis, regulated partially by VEGF is stimulated by environmental enrichment and exercise, learning and antidepressant drugs, and is inhibited by aging (Fig. 3). Abrogation of neurogenesis by exposure to irradiation induces fear and depressive-like behavior (Fabel et al., 2003, Warner-Schmidt and Duman, 2008). On the other hand, the antidepressant drug-induced hippocampal neurogenesis is accompanied by an increase in VEGF expression which leads to a greater VEGFR2 stimulation (Ruiz De Almodovar et al., 2009). Many studies of recent years addresses the problem of the role of neurotrophic factors in pathogenesis of depression and on the effect of antidepressant drugs on neurogenesis and synaptic plasticity (Warner-Schmidt and Duman, 2007, Warner-Schmidt and Duman, 2008).

Neuronal stem cells differentiate to form neurons or glial cells. It was demonstrated in the hippocampus that endothelial cells may influence this process by releasing many factors which induce differentiation of neuronal precursors. Studies have shown that VEGF synthesized by ependymal cells (lining the brain ventricles and the spinal cisterns), acting via VEGFR2, stimulated proliferation of neuronal precursors and enhanced formation of new neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. VEGF given intracerebrally stimulated neurogenesis in the SVZ and SGZ of the DG of the hippocampus (Ogunshola et al., 2002, Wada et al., 2006). In vitro VEGF fostered proliferation of neuronal precursors in mouse cortical cell cultures. Supplementation of these cultures with VEGF increased the diameter of neuronal cells and the number of developing axons (Harms et al., 2010, Rosenstein et al., 2003, Zhu et al., 2003). VEGFR2 antisense oligonucleotides inhibited axonal growth in primary neuronal cultures whereas inhibitors of the PI3K/Akt signaling pathway blocked VEGF-induced cell growth (Khaibullina et al., 2004, Rosenstein et al., 2003, Zhu et al., 2003).

VEGF promotes neurogenesis also by stimulating endothelial cells to the release of neurotrophic factors, like brain-derived neurotrophic factor (BDNF) which aids neuronal survival and integration in the SVZ. Many factors participate or partly determine angiogenic and neurogenic action of VEGF. For instance, erythropoietin promoted angiogenesis by the augmentation of VEGF release from neuronal precursors and regulated VEGFR2 expression in endothelial cells. In vitro proliferation of neuronal stem cells, mediated by VEGF, was contingent upon the presence of basic fibroblast growth factor (bFGF). Also granulocyte colony-stimulating factor (G-CSF) incited neurogenesis in vitro by the elevation of VEGF expression and release from neuronal stem cells. This process requires VEGFR2 since culture supplementation with an antagonist of this receptor caused a blockade of the G-CSF-induced neurogenesis (Namiecińska et al., 2005, Ogunshola et al., 2002, Ruiz De Almodovar et al., 2009).

In hypoxia condition VEGF stimulates growth and survival of Schwann cells forming myelin sheath on axons of peripheral nerves. On the other hand, experiments with a co-culture of endothelial cells, dorsal root ganglia (DRG) cells and Schwann cells showed that both types of nerve cells, by releasing VEGF, promoted endothelial cell differentiation. In the peripheral nervous system, VEGF stimulated proliferation and promoted survival of Schwann cells in explants of the superior cervical ganglia (SCG) and DRG (Mukouyama et al., 2002, Schratzberger et al., 2000, Strokebaum et al., 2004).

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7. The role of VEGF in synaptic plasticity 

Processes of neuronal plasticity encompass changes emerging during learning and memory formation, and during developmental and compensatory (repair) alterations. Brain plasticity depends on the modification of synaptic function, in particular, on efficacy of nervous impulse transmission (Kułak and Sobaniec, 2006).

Research results have indicated that VEGF influences neuronal plasticity in the central nervous system of adult animals. In hippocampal neuronal cultures, VEGF enhanced protein synthesis by modulating Ca2+/calmodulin-dependent protein kinase II (CaMKII), cAMP-responsive element binding (CREB) protein and mammalian Target of Rapamycin kinase (mTOR). It suggests that VEGF can participate in long-term changes in synaptic efficacy. The mechanism of action of VEGF in synaptic plasticity has not been fully elucidated. Locally VEGF fulfills the role of a signal modulator in neurons, by increasing calcium ion influx and/or activating transmembrane domains of tyrosine kinase (Kim et al., 2008, Lee et al., 2009). Long-term potentiation (LTP) is the most often used model of synaptic plasticity. A high frequency stimulation of hippocampal axons in different regions of the brain induces LTP in postsynaptic neurons. Protein kinases, including CaMKII are indispensable for LTP induction (Kułak and Sobaniec, 2006). Experiments on hippocampal slices showed that VEGF treatment before a high-frequency neuron stimulation intensified LTP while a VEGFR2 antagonist reduced this effect (Ruiz De Almodovar et al., 2009, Tassona et al., 2010).

VEGF is released from hippocampal neurons also following N-methyl-d-aspartate (NMDA) receptor activation (Ruiz De Almodovar et al., 2009). It was observed that a single NMDA administration to hippocampal neuronal precursor cell culture increased proliferation and differentiation of these cells. A single NMDA injection in vivo into the dentate gyrus of the hippocampus elevated cell proliferation. NMDA regulated survival of new hippocampal neurons indirectly by releasing such mitogens as VEGF (Joo et al., 2007). NMDA receptor activation in hippocampal neuronal precursor cells, that exhibit VEGF expression, produces immediate calcium ion influx and VEGF release (Joo et al., 2007, Kim et al., 2008).

VEGF can be released from astrocytes by “spilling out” the contents of extracellular vesicles. In vitro, astrocytes form extracellular structures containing fibroblast growth factor-2 (FGF-2), VEGF and β1-integrin. These compounds are released after “spilling out” of the contents of vesicles (Joo et al., 2007, Proia et al., 2008). Although biological significance of VEGF secretion is not known, yet, these observations suggest that VEGF release can postsynaptically affect the action of neurotransmitters (Ruiz De Almodovar et al., 2009).

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8. VEGF as a neuronal and glial protective factor 

VEGF exhibits neurotrophic and neuroprotective activity in the central nervous system and in the peripheral nervous system. It protects cells of the central and peripheral nervous system from death induced by a variety of harmful factors, like hypoxia or deficit of culture medium (Ruiz De Almodovar et al., 2009). These data are depicted in Table 1.

Table 1. VEGF effects on neuronal and glial cells of the central nervous system – in vitro studies.
Cell culturesVEGF-mediated effectsReceptor: pathwayReferenceFs
Neurons
Embryonic cortical neuronsIncreased survivalVEGFR2: MEKOgunshola et al. (2002)
Cerebellar granule cellsSurvival after glutamate, K+ deprivation in culture mediumVEGFR2: Akt/PKCWick et al. (2002)
Cortical neuron precursorsIncreased proliferationVEGFR2: MEK, PLC, PI3KZhu et al. (2003)
Cortical neuronsSurvival after hypoxiaInhibition of caspase-3 activationHolmes et al. (2007)
Primary neuronal culturesInduction of neurite outgrowthVEGFR2: MAPK, PI3K/AktRosenstein et al. (2003)
Primary hippocampal neuronsInduction of neuronal growth and maturationVEGFR2: MAPKKhaibullina et al. (2004)
SVZ neuronal progenitorsSurvival after glutamate-induced toxicityVEGFR2: PI3K/Akt, MEK/ERKJin et al. (2002)
Cerebral cortical culturesIntensified proliferation, differentiation and migrationNot determinedOgunshola et al. (2002)
SVZ neuronal progenitorsIncreased proliferation of neuronal precursors, increased neurogenesisVEGFR2Li et al. (2003)
Motor neuronsSurvival in the presence of mutant SOD1VEFR2: PI3K/AktJin et al. (2002)

Astrocytes, microglia
AstrogliaInduction of proliferation and maturation in serum-free mediumVEGFR1: MAPK/ERK, PI3KMani et al. (2005)
Primary microglial culturesIncreased migration.VEGFR2Mani et al.(2010)
Proliferation and induction of chemotaxisVEGFR1: AktStrokebaum et al. (2004)

Cell line
HN33 (immortalized hippocampal neurons)Survival after hypoxia, serum/glucose deprivation in culture mediumVEGFR2: PI3K/Akt, NFκBMcCloskey et al.(2008)

Abbreviations: Akt, Akt kinase; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; NFκB, nuclear factor kappa B; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLC, phospholipase C; SOD1, superoxide dismutase; SVZ, subventricular zone.

In vitro studies on hypoxia/ischemia models have indicated that neuroprotective action of VEGF is mediated by PI3K/Akt and MAPK/ERK signaling pathways. VEGF inhibited ischemia-induced apoptosis by inhibiting caspase-3 activity and promoted proliferation and migration of neuronal cell precursors (Holmes et al., 2007, Li et al., 2003). The concentration of VEGF and VEGFR2 and the expression of phosphorylated Akt and ERK was increased in a hypoxia model in vitro in cultures of rat cerebellar granule neurons (CGN). The neuroprotective action of VEGF was also demonstrated after CGN exposure to other harmful influences, like elimination of calcium ions from culture medium or toxic concentrations of glutamate (Wick et al., 2002). On the other hand, VEGF stimulated axonal growth and promoted survival of neurons and satellite cells in dorsal root ganglion cultures. It showed also neurotrophic effect in organotypic cell cultures, increasing survival of mesencephalon neurons (Ogunshola et al., 2002). In many instances, VEGF has elicited this effect by signal transduction through VEGFR2 and PI3/Akt pathway (Jin et al., 2002, Lee and Son, 2009, Mani et al., 2010, Ogunshola et al., 2002).

In vitro studies on HN33 cells (mouse hippocampal x cortical neuronal cells) showed that VEGF increased neuronal cell survival under hypoxia, oxidative stress and culture medium deprivation of serum or glucose. VEGF decreased cytotoxic effect of glutamate in hippocampal neuronal cell cultures thereby increasing cell survival. This effect can probably be attributed to the VEGF-provoked inhibition of glutamate-induced hyperexpression of caspase-3, which is a key mediator of apoptotic neuronal cell death. The signal transduction route via VEGFR2 mediated by PI3/Akt and MEK/ERK kinases protects hippocampal neurons against hypoxia-induced damage (McCloskey et al., 2008, Ogunshola et al., 2002, Rosenstein and Krum, 2004). VEGF signal transduction blockade in cortical neuronal cultures led to apoptosis (Ogunshola et al., 2002), while hypoxic response element (HRE) deletion in the VEGF promoter in mice caused degeneration of motor neurons which probably resulted from withdrawal of an indirect neurotrophic effect of VEGF (Jin et al., 2002, Namiecińska et al., 2005). Hence, VEGF produces in vitro an indirect neurotrophic effect on many types of nerve cells, including neurons of the autonomic nervous system, sensory neurons, dopaminergic and hippocampal, cerebellar and cortical nerve cells (Strokebaum et al., 2004).

In vivo studies in rats exposed to CNS hypoxia produced by occlusion of the middle cerebral artery have indicated a rise in VEGF mRNA in the hypoxic area. VEGF administrated directly onto the brain surface resulted in a reduction of the hypoxic area, while its intravenous administration lowered cortical neuronal damage. Exogenous application of VEGF stimulated maturation of new neurons in the hypoxic area and elicited neuroprotective effect. It did not affect angiogenesis and glia proliferation. VEGF at high concentrations was harmful because its proangiogenic action resulted in edema of the stroke zone, which worsened prognosis (Manoonkitiwongsa et al., 2004, Sun et al., 2003). An enhanced VEGF expression in vivo was mostly observed in brains of mice exposed to chronic hypoxia. The increase in VEGF expression was seen both in neurons and glia cells. VEGF had neuroprotective effect on these cells (Wick et al., 2002).

VEGF elevated proliferation and migration of astrocytes. Its mitogenic action on these cells was demonstrated both in cultures of cells isolated from the midbrain and in vivo after intracerebral administration. Reactive astrocytes were shown to express VEGFR1 but not VEGFR2 protein. It suggests that VEGFR1 mediates the mitogenic VEGF action on astrocytes. VEGFR1 activation by VEGF participated also in microglia stimulation, migration and proliferation (Strokebaum et al., 2004).

VEGFR2 signaling pathway is mostly connected with the VEGF action on Schwann cells and peripheral neurons whereas VEGFR1 mediates the VEGF effects on astrocytes and microglia (Jin et al., 2002, Strokebaum et al., 2004).

By its neuroprotective action, VEGF influences hippocampus-dependent processes, like learning and memory (McCloskey et al., 2005).

Changes in VEGF concentration were demonstrated to occur in such diseases as cerebral stroke, amyotropic lateral sclerosis, Parkinson’s disease and Alzheimer’s disease, which makes VEGF a potential target for neuroprotective drugs (Ruiz De Almodovar et al., 2009).

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9. Implication of VEGF in the mechanism of action of antidepressant drug 

Major depressive disorder (MDD) belongs to the most common psychiatric disorders worldwide. Depression is a devastating disease, affecting about 10% of human population. Depressive disorders are a heterogenic group of diseases. Some patients respond to routine pharmacological treatment while others are resistant to antidepressant drugs and require electroconvulsive therapy (ECT). A majority of antidepressant drugs act through increasing the activity of monoaminergic systems of the brain. It is thought that these changes are essential for the mechanism of action of this group of drugs but they do not fully explain their clinical effects (Tsai et al., 2009, Viikki et al., 2010, Warner-Schmidt and Duman, 2007).

In the last decade, investigations focusing on mood disturbances have been extended to brain neuroplasticity. These studies concentrate principally on brain-derived neurotrophic factor (BDNF). Recent studies suggest that VEGF can be disregulated in stress and depressive states. Neurogenic and neurotrophic hypothesis of depression assumes that development of this disease is, at least partially, related to the reduced neurogenesis and/or depletion of neurotrophic factors which can lead to structural deformity and functional impairment of the nervous system. It is believed that a low concentration of VEGF and other trophic factors, in particular BNDF, can contribute to progression of depression (Bergström et al., 2008, Kahl et al., 2009, Warner-Schmidt and Duman, 2007).

A strong positive correlation between the incidence of cardiovascular diseases and depression suggests a potential role of vascular disorders in depression. VEGF can be a molecular link between these two diseases. It has been suggested that the induction of endothelial cell proliferation and angiogenesis can be an important factor in the treatment of these forms of depression which are accompanied by vascular disorders. VEGF can become a biomarker of such depressive states (Greene et al., 2009, Warner-Schmidt and Duman, 2007, Warner-Schmidt and Duman, 2008).

Studies on the effect of antidepressant drugs on VEGF deal mostly with the hippocampus, which is a limbic brain structure implicated in pathogenesis of depression and also important for its therapy. Depressed patients were shown to have a lower hippocampus volume. This effect was negatively correlated with duration of the therapy with antidepressant drugs (Greene et al., 2009). Table 2 demonstrates the results of experimental studies concerning the effects of antidepressants on VEGF in rat hippocampus.

Table 2. Influence of antidepressant drugs on VEGF gene expression and the level of VEGF protein in the rat hippocampus – in vivo studies.
Test/modelDosage of antidepressant drug or VEGFR antagonistDuration of treatmentEffectsReferences
CUS, NSF, FSTFluoxetine (5mg/kg, i.p.),21daysIncreased VEGF protein levelsGreene et al. (2009)
SU5416 (4nM, i.c.v.)VEGFR antagonist on the 14, 16, 18, 20dayIncreased expression of VEGF mRNA in the GCL
SU1498 (4nM, i.c.v.)VEGFR antagonists block behavioral effects of fluoxetine
Sertraline (10mg/kg, i.p.)21daysIncreased VEGF protein levelsGreene et al. (2009)
Amitriptyline (5mg/kg, b.i.d., i.p.)
Venlafaxine (15mg/kg, b.i.d, i.p.)
LH, FSTFluoxetine (5mg/kg, i.p.)14daysSU5416 blocks the behavioral effects of fluoxetine and desipramineWarner-Schmidt and Duman (2007)
SU5416 (4 nM, i.c.v.)SU5416 on the 8, 10, 12, 14day
LH, FSTDesipramine (10mg/kg, i.p.)6daysIncreased expression of VEGF mRNA in the GCLWarner-Schmidt and Duman (2007)
SU5416 (4nM, i.c.v.)SU5416 for the last 3days
NSFDesipramine (7.5mg/kg, b.i.d., i.p.)21daysSU5416 blocks the antidepressant effect of desipramineWarner-Schmidt and Duman (2007)
SU5416 (4nM, i.c.v.)SU5416 on the 12, 15, 18, 21day
CUSDesipramine (7.5mg/kg, b.i.d., i.p.)28daysSU5416 blocks the ability of desipramine to increase sucrose preference.Warner-Schmidt and Duman (2007)
SU5416 (4nM, i.c.v.)SU5416 for the 28days

Abbreviations: CUS, chronic unpredictable stress; FST, forced swim test; GCL, granular cell layer; LH, learned helplessness; NSF, novelty suppressed feeding.

Experiments in animal models of depression such as chronic unpredictable stress (CUS) and novelty suppressed feeding (NSF) indicated that VEGF expression in the hippocampus was induced by different antidepressant drugs (fluoxetine, sertraline, amitriptyline, desipramine and venlafaxine) and by electroseizures. VEGF action via VEGFR2 proved indispensable for cellular and behavioral responses to the above mentioned antidepressant drugs (Elfving et al., 2010, Greene et al., 2009, Warner-Schmidt and Duman, 2007). When rats were subjected to CUS, treated with fluoxetine or desipramine for 14days and tested for VEGF expression, both antidepressant drugs elevated VEGF mRNA level in the granule cell layer (GCL) of the hippocampus vs. control. VEGF protein level was also increased in tissue extracts from the hippocampus (Greene et al., 2009). Antidepressant drug action on VEGF is mediated by CREB protein. On the one hand, it is known that antidepressant drugs increase CREB activity and expression in GCL and on the other, that the VEGF promoter contains CREB activation (Greene et al., 2009, Kim et al., 2008).

Studies in the CUS or the NSF model, in which rats were injected sertraline, amitriptyline or venlafaxine for 21days showed elevated levels of VEGF protein in the hippocampal tissue extracts (Greene et al., 2009). Results of the studies with the VEGFR2 antagonists (SU5416, SU1498) confirmed the hypothesis about the significance of VEGF for antidepressant therapy. When administered intraventricularly 30min before electroshocks, they completely (SU5416) or markedly (SU1498) blocked the electroseizure-induced SGZ cell proliferation. In the next experiment, VEGFR2 antagonists were administered four times in the last week of fluoxetine and desipramine treatment. The drugs were injected intraperitoneally: fluoxetine for 14days and desipramine for 21days. SU5416 completely blocked both fluoxetine and desipramine effects (Warner-Schmidt and Duman, 2007). These results confirm that the VEGFR2-mediated signaling is crucial for the action of both tested antidepressant drugs. They also suggest that an increased endothelial cell proliferation and hippocampal neurogenesis together with augmented VEGF expression observed after antidepressant drug treatment are significant for the therapeutic action of both drugs (Ruiz De Almodovar et al., 2009). The upregulation of VEGF expression indicated that it mediated proliferative action of antidepressant drugs (Greene et al., 2009, Tassona et al., 2010, Warner-Schmidt and Duman, 2007). Taken together, these studies indicate that VEGF mediates both cytogenic and behavioral effects of antidepressive treatment such as ECT and different antidepressants.

Experimental data suggest that neurogenesis is regulated by interaction between nerve and endothelial cells and/or factors released from these cells, including VEGF. Stimulation of neuronal VEGF could also contribute to neurogenic responses, as well as neuroprotective- and neuroplasticity-related effects induced by antidepressants. The results of the studies using the forced swim test (FST) and the learned helplessness (LH) also confirm that VEGF-mediated signaling is essential for neurogenic and behavioral action of antidepressant drugs. FST and LH belong to classical behavioral tests used for screening drugs for antidepressant potential. It was shown that the central VEGF infusion mimicked antidepressant drug effects in these tests while VEGFR2 blockade by SU5416 treatment reduced desipramine effect (Ventriglia et al., 2009, Warner-Schmidt and Duman, 2007). It also appeared that VEGF mediated the behavioral response to fluoxetine (Warner-Schmidt and Duman, 2008). However, value of data obtained using such tests as FST and LH is limited because already a single treatment or a few doses of an antidepressant drug produces effects observable in these tests which does not agree with the fact that a significant clinical improvement can be usually achieved after a 2-week therapy. It is believed that the delay in manifestation of the therapeutic effect observed in clinical practice can be connected with cellular and/or molecular adaptive processes in neurons (e.g. activation of cAMP pathway) (Lucas et al., 2007, Tamburella et al., 2009). In addition, it is congruent with the time required for induction of neurogenesis encompassing such processes as proliferation, maturation and differentiation of new neurons which was proven in the above-mentioned behavioral tests (Greene et al., 2009). The short time needed for manifestation of the behavioral effect of antidepressant drugs in the FST and the LH does not correlate with the time required for neurogenesis. It suggests that VEGF impacts not only on neurogenesis but also on other neurogenesis-independent neuronal processes, e.g. neuroplasticity. It has not been confirmed yet which brain cells are the most susceptible to VEGF action induced by antidepressant drugs and which mediate behavioral effects of exogenous VEGF (Warner-Schmidt and Duman, 2008).

It is known that the mechanism of action of antidepressant drugs implicates an increase in mostly serotonergic system activity (5-HT), and selective serotonin reuptake inhibitors (SSRI) are the first choice drugs in MDD therapy. However, the role of different types of 5-HT receptors in pathophysiology and treatment of depression has not been fully elucidated, yet. Results of in vitro studies indicate that 5-HT system activity affects VEGF expression which at least partially mediates behavioral response to antidepressant drugs. A single administration of the human high-affinity and high-selectivity 5-HT4 receptor agonist, SL65.0155, shortened immobility time in the FST and concomitantly elevated VEGF expression and changed hippocampal concentrations of pCREB, BDNF, and Bcl-2 and Bax proteins (Tamburella et al., 2009, Vicale et al., 2006). It is also known that by 5-HT2 receptor activation, 5-HT stimulates VEGF expression thereby inducing endothelial cell proliferation. In addition, study results indicate that fluoxetine action is underlain by 5-HT2 receptor stimulation (Warner-Schmidt and Duman, 2007).

Electroconvulsive therapy belongs to the quickest and the most efficient therapeutic methods in depression. Cellular mechanism of ECT efficacy is not fully understood. Recent studies have demonstrated that ECT, like antidepressant drugs, increased hippocampal neurogenesis in rats by promoting the expression of trophic factors, like BDNF and VEGF. The VEGF mRNA expression was elevated in the hippocampus 6 and 24h after ECT session and returned to basal values after 72h. It suggests that VEGF signaling pathways are essential for induction of cell proliferation which follows electroconvulsions (Madsen et al., 2000, Segi-Nishida et al., 2008, Viikki et al., 2010, Warner-Schmidt and Duman, 2007).

Results of clinical studies on VEGF in depressed patients are unequivocal. Serum VEGF concentration was increased in depressed patients with comorbid borderline personality disorder (Kahl et al., 2009). However, two other studies did not find differences in serum or plasma VEGF concentration between depressed patients and control subjects (Ventriglia et al., 2009). Despite the fact that VEGF seems to be linked with psychiatric disorders, it has not been resolved whether serum VEGF concentration reflects its level in the central nervous system (Elfving et al., 2010).

At least 25 VEGF gene polymorphisms are known. Up till now only one paper addressed an association between VEGF 2578 C/A polymorphism and depressive disorder. Incidence of this polymorphism was examined in the Japanese population. The results demonstrated a higher expression of the mentioned VEGF gene polymorphism in peripheral leucocytes of depressed patients vs. age- and sex-matched control group. It is thought that a higher level of VEGF mRNA can result from oxidative stress in the organism (Iga et al., 2007). However, the next studies did not show a significant difference in plasma VEGF level between depressed patients treated with antidepressant drugs or untreated depressed patients and control group (Viikki et al., 2010).

Since it is believed that differences in therapeutic efficacy of antidepressant drugs in depressed patients can be of genetic origin, the studies currently in progress aim to identify genetic markers predictive of efficacy of this group of drugs in a patient. The results on the relationship between response to SSRI and a polymorphism in the promoter region of the serotonin transporter gene in MDD patients are the most promising. However, no significant difference in the allele frequency or in the distribution of the VEGF polymorphism-bearing genotypes were found between patients efficiently treated with fluoxetine or citalopram and pharmacologically untreated patients (Blumberg et al., 2008, Tsai et al., 2009). Studies on 2578C allele have revealed that this allele is more frequent in patients resistant to pharmacotherapy of depression than in a control population (Iga et al., 2007).

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10. Conclusions 

Recently, VEGF potential as a trophic factor, impacting on both endothelial cells and brain cells, either neurons or glia, has become a focus of neuropsychiatric and neuropharmacological studies. It was revealed that antidepressant drugs induced VEGF expression in the hippocampus. Moreover, in animal models of depression, VEGF-mediated signaling via VEGFR2 was essential for cellular and behavioral response to antidepressant drugs (Iga et al., 2007, Warner-Schmidt and Duman, 2007, Warner-Schmidt and Duman, 2008). It is currently believed that VEGF can indeed be implicated in the action of these drugs since this trophic factor is beneficial for: (1) neurogenesis, (2) survival of nerve cells, (3) synaptic plasticity, and (4) proliferation of vascular endothelial cells induced by antidepressant drugs (Greene et al., 2009, Ventriglia et al., 2009). Studies in the NSF model demonstrated that the VEGF-induced enhancement of neurogenesis was obligatory for manifestation of behavioral effects of antidepressant drugs (Greene et al., 2009). However, the cause of the VEGF-stimulated changes in the FST and LH tests, that are similar to the effects of antidepressant drugs, remains unexplained, which suggests that VEGF produces “antidepressant effect” by influencing other cellular processes, in addition to neurogenesis (Greene et al., 2009, Warner-Schmidt and Duman, 2007, Warner-Schmidt and Duman, 2008). In the light of the data obtained so far, it seems purposeful to determine regions of the brain and signaling pathways mediating antidepressant action of VEGF. Ascertainment of signaling routes engaged in neurogenic and behavioral activities of VEGF can help identify new targets of potential antidepressant drugs. In the future, it appears reasonable to perform clinical studies in order to analyze plasma VEGF level in patients suffering from different types of depression and to identify polymorphisms that could be used as biomarkers of depression. It seems also interesting to explain the role of VEGF as a potential molecular link between depression and circulatory diseases. Results of studies on VEGF appear to be an important complement to the neurotrophic/neurogenic hypothesis of action of antidepressant drugs and allow for gaining a deeper insight into their action at the cellular level. A better understanding of the cellular mechanisms is a chance for development of a more quick acting and more efficient therapy of depression.

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PII: S0143-4179(11)00044-8

doi:10.1016/j.npep.2011.05.005

Neuropeptides
Volume 46, Issue 1 , Pages 1-10, February 2012

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