Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling (original) (raw)
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Brain Pathology, 2006
Hypoxia as well as global and focal ischemia are strong activators of neurogenesis in the adult mammalian central nervous system. Here we show that the hypoxia-inducible vascular endothelial growth factor (VEGF) and its receptor VEGFR-2/Flk-1 are expressed in clonally-derived adult rat neural stem cells in vitro. VEGF stimulated the expansion of neural stem cells whereas blockade of VEGFR-2/Flk-1-kinase activity reduced neural stem cell expansion. VEGF was also infused into the lateral ventricle to study changes in neurogenesis in the ventricle wall, olfactory bulb and hippocampus. Using a low dose (2.4 ng/d) to avoid endothelial proliferation and changes in vascular permeability, VEGF stimulated adult neurogenesis in vivo. After VEGF infusion, we observed reduced apoptosis but unaltered proliferation suggesting a survival promoting effect of VEGF in neural progenitor cells. Strong expression of VEGFR-2/Flk-1 was detected in the ventricle wall adjacent to the choroid plexus, a site of significant VEGF production, which suggests a paracrine function of endogenous VEGF on neural stem cells in vivo. We propose that VEGF acts as a trophic factor for neural stem cells in vitro and for sustained neurogenesis in the adult nervous system. These findings may have implications for the pathogenesis and therapy of neurodegenerative diseases.
Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo
Proceedings of the National Academy of Sciences, 2002
Vascular endothelial growth factor (VEGF) is an angiogenic protein with neurotrophic and neuroprotective effects. Because VEGF promotes the proliferation of vascular endothelial cells, we examined the possibility that it also stimulates the proliferation of neuronal precursors in murine cerebral cortical cultures and in adult rat brain in vivo. VEGF (>10 ng͞ml) stimulated 5-bromo-2deoxyuridine (BrdUrd) incorporation into cells that expressed immature neuronal marker proteins and increased cell number in cultures by 20 -30%. Cultured cells labeled by BrdUrd expressed VEGFR2͞Flk-1, but not VEGFR1͞Flt-1 receptors, and the effect of VEGF was blocked by the VEGFR2͞Flk-1 receptor tyrosine kinase inhibitor SU1498. Intracerebroventricular administration of VEGF into rat brain increased BrdUrd labeling of cells in the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), where VEGFR2͞Flk-1 was colocalized with the immature neuronal marker, doublecortin (Dcx). The increase in BrdUrd labeling after the administration of VEGF was caused by an increase in cell proliferation, rather than a decrease in cell death, because VEGF did not reduce caspase-3 cleavage in SVZ or SGZ. Cells labeled with BrdUrd after VEGF treatment in vivo include immature and mature neurons, astroglia, and endothelial cells. These findings implicate the angiogenesis factor VEGF in neurogenesis as well.
Vascular regulation of adult neurogenesis under physiological and pathological conditions
Frontiers in Neuroscience, 2014
Neural stem cells in the mammalian adult brain continuously produce new neurons throughout life. Accumulating evidence in rodents suggests that various aspects of adult neurogenesis, including the genesis, migration, and maturation of new neurons, are regulated by factors derived from blood vessels and their microenvironment. Brain injury enhances both neurogenesis and angiogenesis, thereby promoting the cooperative regeneration of neurons and blood vessels. In this paper, we briefly review the mechanisms for the vascular regulation of adult neurogenesis in the ventricular-subventricular zone under physiological and pathological conditions, and discuss their clinical potential for brain regeneration strategies.
Vascular endothelial growth factor promotes neurite maturation in primary CNS neuronal cultures
Developmental Brain Research, 2004
Recent studies have demonstrated that vascular endothelial growth factor (VEGF) and its receptor VEGFR2 (flk-1) are expressed by neurons during development and following hypoxic -ischemic events. Moreover, fetal CNS tissue explants exposed to exogenous VEGF exhibit increased neuronal Map-2 expression, suggesting that VEGF could have an effect on neuronal maturation. To determine whether this effect is of a direct nature, we examined the expression of Map-2 in the presence of VEGF in primary CNS neuronal cultures. After 3 days in culture, a statistically significant dose-dependent increase in the length of Map-2(+) processes was observed, with the peak occurring at 10 ng/ml of VEGF. Immunohistochemical analysis of the cultures demonstrated the presence of VEGFR2 after VEGF treatment, as well as the expression of the VEGF receptor VEGFR1 (flt-1). Treatment of the cultures with antisense oligonucleotides against VEGFR2, but not against VEGFR1, abolished the effect of VEGF on the length of Map-2(+) processes. RT-PCR analyses of Map-2 and VEGFR1 indicated that mRNAs of these two genes are upregulated in the presence of VEGF. The addition of wortmannin, an inhibitor of PI3K/Akt signaltransduction pathway, to the media did not affect the VEGF-dependent increase in Map-2(+) length. In contrast PD98059, which inhibits the MAPK pathway, partially abolished this effect of VEGF. These experiments suggest that VEGF has a direct effect on neuronal growth and maturation under normoxic conditions during CNS development, which is mediated by the VEGFR2 receptor via the MAPK pathway. D
The Journal of Neuroscience the Official Journal of the Society For Neuroscience, 2003
Because gene knock-outs of VEGF and its receptors flk-1 and flt-1 result in early embryonic lethality, determining roles for VEGF in CNS development has been particularly difficult. Recent studies have shown that VEGF is upregulated after various injuries to the adult brain and that the cytokine affords protection to cultured neurons affected by oxidative or excitotoxic stress. The present study demonstrates, for the first time, that VEGF is directly neurotrophic to CNS neurons in culture. We applied VEGF to normoxic fetal organotypic cortical explants as a model of CNS neuropil, in addition to primary cortical neurons, to assess direct growth effects absent vascular or astroglial activity. We found that VEGF provided a significant dose-responsive increase in the neuronal microtubule markers TUJ1 and MAP-2, as well as mRNA for MAP-2 and flk-1. Antisense oligodeoxynucleotides to flk-1, but not flt-1, inhibited neuritic outgrowth, whereas inhibitors of the signaling pathways MEK1 and P13-AKT both abrogated VEGF-induced growth. VEGF applied to primary cortical neurons produced significant increases in neuronal cell body diameter and the number of emerging neurites mediated by flk-1. Possibly, VEGF achieves its effects by acting on the neuronal microtubular content, which is involved with growth, stability and maturation. Several studies have now shown that VEGF is neurotrophic and neuroprotective independent of a vascular component; we suggest that VEGF plays seminal pleiotrophic roles in CNS development and repair.
Microvascular Influences on Progenitor Cell Mobilization and Fate in the Adult Brain
Blood-Brain Barriers
Introduction 41 2.2 Brain Angiogenesis 42 2.2.1 Hypoxia-Regulated HIF-1 in the Development of the Brain 42 2.2.2 Hypoxia-Inducible Factor 43 2.2.3 Hypoxia-Induced VEGF 46 2.2.4 Other Neuroglia-Derived Angiogenic Factors 47 2.3 Oxygenation in the Brain: Brain Barriergenesis 49 2.3.1 Cellular and Molecular Responses Following Brain Oxygenation 49 2.3.2 Role of src-Suppressed C Kinase Substrate in the Induction of Barriergenesis 50 2.3.3 Barriergenic Factors in Perivascular Astrocytes and Pericytes Following Brain Oxygenation 51 2.4 Perspectives 53 References 55 3 Microvascular Influences on Progenitor Cell Mobilization and Fate in the Adult Brain 61 Christina Lilliehook and Steven A. Goldman 3.1 Introduction 61 3.2 Angiogenic Foci Persist in the Adult Brain 61 3.3 Neurotrophic Cytokines Can Be of Vascular Origin 62 3.4 Angiogenesis and Neurogenesis are Linked in the Adult Avian Brain 63 3.5 Angiogenesis-Neurogenesis Interactions in the Adult Mammalian Brain 65 3.
Vascular adventitia generates neuronal progenitors in the monkey hippocampus after ischemia
Hippocampus, 2004
In the adult hippocampus, neurogenesis proceeds in the subgranular zone (SGZ) of the dentate gyrus (DG), but not in the cornu Ammonis (CA). Recently, we demonstrated in monkeys that transient brain ischemia induces an increase of the neuronal progenitor cells in the SGZ, but not in CA1, in the second week after the insult. To identify the origin of primary neuronal progenitors in vivo, we compared the postischemic monkey DG and CA1, using light and electron microscopy, focusing on specific phenotype markers, as well as the expression of neurotrophic factors. Laser confocal microscopy showed that 1–3% of 5-bromo-2′-deoxyuridine (BrdU)-positive cells in the SGZ after 2–96 h labeling were also positive for neuronal markers such as TUC4, βIII tubulin, and NeuN on days 9 and 15. In contrast, despite the presence of numerous BrdU-positive cells, CA1 showed no neurogenesis at any time points, and all the progenitors were positive for glial markers: Iba1 or S-100β on days 4, 9, and 15. Highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive cells were abundant in the SGZ, but were absent in CA1. On day 9, most of the immature neurons positive for βIII-tubulin in SGZ showed an increase in PSA-NCAM immunoreactivity. The immunoreactivity of brain-derived neurotrophic factor (BDNF) was abundant at the vascular adventitia of the SGZ, but was absent at the adventitia of CA1. BrdU-positive progenitor cells were frequently seen in the vicinity of proliferating blood vessels. Ultrastructural analysis indicated that most of the neuronal progenitor cells and microglia originated from the pericytes of capillaries and/or adventitial cells of arterioles (called vascular adventitia). The detaching adventitial cells showed mitotic figures in the perivascular space, and the resultant neuronal progenitor cells made contact with dendritic spines associated with synaptic vesicles or boutons. These data implicate the vascular adventitia as a novel potential source of neuronal progenitor cells in the postischemic primate SGZ. © 2004 Wiley-Liss, Inc.
Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis
Genes & Development, 2011
Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astro...
Journal of Neurotrauma, 2010
Stimulating the endogenous repair process after traumatic brain injury (TBI) can be an important approach in neuroregenerative medicine. Vascular endothelial growth factor (VEGF) is one of the molecules that can increase de novo hippocampal neurogenesis. Here, we tested whether VEGF signaling through Flk1 (VEGF receptor 2) is involved in the neurogenic process after experimental TBI. We found that Flk1 is expressed both by neuroblasts in the subgranular layer (SGL) and by maturing granule neurons in the adult dentate gyrus (DG) of the hippocampus. After lateral fluid percussion TBI (LFP-TBI) in the rat, we detected elevated VEGF levels and also increased numbers of de novo neurons in the ipsilateral DG. To test the involvement of VEGF and Flk1 in the neurogenic process directly, we delivered recombinant VEGF or SU5416, an inhibitor to Flk1, into the ipsilateral cerebral ventricle of injured animals. We found that VEGF infusion significantly increased the number of BrdUþ=Prox1þ new neurons, decreased the number of TUNELþ cells, but did not change the number of BrdUþ newborn cells per se. Infusion with SU5416 caused no significant changes. Our results suggest that (a) VEGF is a part of the molecular signaling network that mediates de novo hippocampal neurogenesis after TBI; (b) VEGF predominantly mediates survival of de novo granule neurons rather than proliferation of neuroblasts in the injured brain; and (c) additional VEGF receptor(s) and=or other molecular mechanism(s) are also involved in mediating increased neurogenesis following injury.