VEGF in the nervous system

Vascular endothelial growth factor (VEGF, VEGFA) is critical for blood vessel growth in 
the developing and adult nervous system of vertebrates. Several recent studies demonstrate that VEGF also promotes neurogenesis, neuronal patterning, neuroprotection and glial growth. For example, VEGF treatment of cultured neurons enhances survival and neurite growth independently of blood vessels. Moreover, evidence is emerging that VEGF guides neuronal migration in the embryonic brain and supports axonal and arterial co-patterning in the developing skin. Even though further work is needed to understand the various roles of VEGF in the nervous system and to distinguish direct neuronal effects from indirect, vessel-mediated effects, VEGF can be considered a promising tool to promote neuronal health and nerve repair. Note: Previously published in VEGF in Development, edited by Christiana Ruhrberg. Landes Bioscience and Springer Science+Business Media 2008; pp. 91-103.

[1]  A. Kolodkin,et al.  Steering Clear of Semaphorins: Neuropilins Sound the Retreat , 1997, Neuron.

[2]  C. Cepko,et al.  Flk-1, a Receptor for Vascular Endothelial Growth Factor (VEGF), Is Expressed by Retinal Progenitor Cells , 1996, The Journal of Neuroscience.

[3]  R. Alderson,et al.  Vascular Endothelial Cell Growth Factors Promote the In Vitro Development of Rat Photoreceptor Cells , 2000, The Journal of Neuroscience.

[4]  G. Breier,et al.  Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. , 1992, Development.

[5]  T. Kitsukawa,et al.  Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. , 1995, Development.

[6]  K. Jin,et al.  Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Rosenstein,et al.  Astrocyte growth effects of vascular endothelial growth factor (VEGF) application to perinatal neocortical explants: receptor mediation and signal transduction pathways , 2005, Experimental Neurology.

[8]  M. Tessier-Lavigne,et al.  Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function , 2003, Nature.

[9]  W. Stewart,et al.  Paracrine and Autocrine Functions of Neuronal Vascular Endothelial Growth Factor (VEGF) in the Central Nervous System* , 2002, The Journal of Biological Chemistry.

[10]  S. Shih,et al.  Nonvascular role for VEGF: VEGFR-1, 2 activity is critical for neural retinal development. , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  C. Ware,et al.  Androgen Receptor YAC Transgenic Mice Recapitulate SBMA Motor Neuronopathy and Implicate VEGF164 in the Motor Neuron Degeneration , 2004, Neuron.

[12]  C. Ruhrberg Growing and shaping the vascular tree: multiple roles for VEGF , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[13]  D. Hu,et al.  Expression of angiogenesis-related genes during retinal development. , 2006, Gene expression patterns : GEP.

[14]  N. Ferrara,et al.  The biology of VEGF and its receptors , 2003, Nature Medicine.

[15]  W. Risau,et al.  Mechanisms of angiogenesis , 1997, Nature.

[16]  H. Dvorak,et al.  Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. , 1995, The American journal of pathology.

[17]  J. Bolz,et al.  Semaphorin 3A–Vascular Endothelial Growth Factor-165 Balance Mediates Migration and Apoptosis of Neural Progenitor Cells by the Recruitment of Shared Receptor , 2001, The Journal of Neuroscience.

[18]  Peter Carmeliet,et al.  Blood vessels and nerves: common signals, pathways and diseases , 2003, Nature Reviews Genetics.

[19]  Shay Soker,et al.  Neuropilin-1 Is Expressed by Endothelial and Tumor Cells as an Isoform-Specific Receptor for Vascular Endothelial Growth Factor , 1998, Cell.

[20]  N. Ferrara,et al.  The biology of vascular endothelial growth factor. , 1997, Endocrine reviews.

[21]  M. Eddleston,et al.  Molecular profile of reactive astrocytes—Implications for their role in neurologic disease , 1993, Neuroscience.

[22]  T. Palmer,et al.  Vascular niche for adult hippocampal neurogenesis , 2000, The Journal of comparative neurology.

[23]  L. Olson,et al.  Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury , 2003, Neuroscience.

[24]  Kenneth J. Hillan,et al.  Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene , 1996, Nature.

[25]  Thomas M. Jessell,et al.  Semaphorin 3E and Plexin-D1 Control Vascular Pattern Independently of Neuropilins , 2005, Science.

[26]  J. Alroy,et al.  Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy , 2000, Nature Medicine.

[27]  Holger Gerhardt,et al.  Neuropilin‐1 is required for endothelial tip cell guidance in the developing central nervous system , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[28]  M. Vitek,et al.  Vascular endothelial growth factor rescues hippocampal neurons from glutamate‐induced toxicity: signal transduction cascades , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  Jonathan A Raper,et al.  Semaphorins and their receptors in vertebrates and invertebrates , 2000, Current Opinion in Neurobiology.

[30]  M. Kanje,et al.  Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk‐1 receptor , 2000, The European journal of neuroscience.

[31]  S. Soker,et al.  Neuropilin-1 Mediates Collapsin-1/Semaphorin III Inhibition of Endothelial Cell Motility , 1999, The Journal of cell biology.

[32]  Brenden Chen,et al.  VEGF activates divergent intracellular signaling components to regulate retinal progenitor cell proliferation and neuronal differentiation , 2006, Development.

[33]  D. van der Kooy,et al.  Vascular Endothelial Growth Factor Directly Inhibits Primitive Neural Stem Cell Survival But Promotes Definitive Neural Stem Cell Survival , 2006, The Journal of Neuroscience.

[34]  Holger Gerhardt,et al.  Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. , 2002, Genes & development.

[35]  Joseph B. Kearney,et al.  The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis. , 2004, Blood.

[36]  M. Klagsbrun,et al.  VEGF is required for the maintenance of dorsal root ganglia blood vessels but not neurons during development , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  P. Carmeliet,et al.  Vascular and neuronal effects of VEGF in the nervous system: implications for neurological disorders. , 2002, Seminars in cell & developmental biology.

[38]  E. Oldfield,et al.  Vascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brain. , 1999, Journal of neuropathology and experimental neurology.

[39]  H. Hammes,et al.  Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor , 2004, Thrombosis and Haemostasis.

[40]  M Chopp,et al.  VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. , 2000, The Journal of clinical investigation.

[41]  David J. Anderson,et al.  Sensory Nerves Determine the Pattern of Arterial Differentiation and Blood Vessel Branching in the Skin , 2002, Cell.

[42]  J. Rossant,et al.  Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium , 1995, Nature.

[43]  I. Fariñas,et al.  Pigment epithelium–derived factor is a niche signal for neural stem cell renewal , 2006, Nature Neuroscience.

[44]  Christoph Schmitz,et al.  Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS , 2005, Nature Neuroscience.

[45]  Jeffrey M. Rosenstein,et al.  New roles for VEGF in nervous tissue—beyond blood vessels , 2004, Experimental Neurology.

[46]  S. D. Fraser,et al.  Semaphorin-plexin signaling guides patterning of the developing vasculature. , 2004, Developmental cell.

[47]  M. Chopp,et al.  Up-Regulation of Neuropilin-1 in Neovasculature after Focal Cerebral Ischemia in the Adult Rat , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[48]  G. Terenghi,et al.  VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy , 2000, Journal of anatomy.

[49]  T. Yagi,et al.  A requirement for neuropilin-1 in embryonic vessel formation. , 1999, Development.

[50]  M. Klagsbrun,et al.  Neurovascular congruence results from a shared patterning mechanism that utilizes Semaphorin3A and Neuropilin-1. , 2003, Developmental biology.

[51]  J. Kiss,et al.  VEGF is a chemoattractant for FGF-2–stimulated neural progenitors , 2003, The Journal of cell biology.

[52]  Janet Rossant,et al.  Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice , 1995, Nature.

[53]  V. Arolt,et al.  Vascular Endothelial Growth Factor Protects Cultured Rat Hippocampal Neurons against Hypoxic Injury via an Antiexcitotoxic, Caspase-Independent Mechanism , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[54]  K. Alitalo,et al.  VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia , 2003, The Journal of cell biology.

[55]  Peter Carmeliet,et al.  VEGF: a critical player in neurodegeneration. , 2004, The Journal of clinical investigation.

[56]  C. Ruhrberg,et al.  Selective requirements for NRP1 ligands during neurovascular patterning , 2007, Development.

[57]  Till Acker,et al.  Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration , 2001, Nature Genetics.

[58]  P. Carmeliet,et al.  VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death , 2003, Nature Genetics.

[59]  T. Noda,et al.  Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[60]  J. Krum,et al.  Inhibition of endogenous VEGF impedes revascularization and astroglial proliferation: roles for VEGF in brain repair , 2003, Experimental Neurology.

[61]  W. Silverman,et al.  Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures , 1999, Neuroscience.

[62]  J. Bolz,et al.  Semaphorins act as attractive and repulsive guidance signals during the development of cortical projections. , 1998, Development.

[63]  T. Bär,et al.  Patterns of vascularization in the developing cerebral cortex. , 1983, Ciba Foundation symposium.

[64]  G. Lundborg,et al.  Vascular Endothelial Growth Factor Has Neurotrophic Activity and Stimulates Axonal Outgrowth, Enhancing Cell Survival and Schwann Cell Proliferation in the Peripheral Nervous System , 1999, The Journal of Neuroscience.

[65]  Chenghua Gu,et al.  Peripheral nerve-derived VEGF promotes arterial differentiation via neuropilin 1-mediated positive feedback , 2005, Development.

[66]  T. Acker,et al.  Direct Stimulation of Adult Neural Stem Cells In Vitro and Neurogenesis In Vivo by Vascular Endothelial Growth Factor , 2004, Brain pathology.

[67]  N. Ferrara VEGF: an update on biological and therapeutic aspects. , 2000, Current opinion in biotechnology.

[68]  Steven A. Goldman,et al.  Coordinated Interaction of Neurogenesis and Angiogenesis in the Adult Songbird Brain , 2002, Neuron.

[69]  W. Silverman,et al.  Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and in vivo. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[70]  K. Jin,et al.  Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[71]  Lieve Moons,et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele , 1996, Nature.

[72]  G. Lundborg,et al.  Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts , 1999, Brain Research.

[73]  A. Kolodkin,et al.  Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. , 2004, Genes & development.

[74]  E. Wagner,et al.  Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling. , 2003, Developmental biology.

[75]  J. Rosenstein,et al.  Neurotrophic Effects of Vascular Endothelial Growth Factor on Organotypic Cortical Explants and Primary Cortical Neurons , 2003, The Journal of Neuroscience.

[76]  K. Jin,et al.  Induction of vascular endothelial growth factor and hypoxia-inducible factor-1α by global ischemia in rat brain , 2000, Neuroscience.

[77]  Yasuto Itoyama,et al.  Reduction of Ischemic Damage by Application of Vascular Endothelial Growth Factor in Rat Brain after Transient Ischemia , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[78]  R. Pallini,et al.  Promotion of regeneration of corticospinal tract axons in rats with recombinant vascular endothelial growth factor alone and combined with adenovirus coding for this factor. , 2002, Journal of neurosurgery.

[79]  J. Rosenstein,et al.  Vascular endothelial growth factor promotes neurite maturation in primary CNS neuronal cultures. , 2004, Brain research. Developmental brain research.

[80]  N. van Bruggen,et al.  VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. , 1999, The Journal of clinical investigation.

[81]  J. Rosenstein,et al.  Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain , 2002, Neuroscience.

[82]  K. Alitalo,et al.  Neural guidance molecules regulate vascular remodeling and vessel navigation. , 2005, Genes & development.

[83]  K. Jin,et al.  VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. , 2003, The Journal of clinical investigation.

[84]  Bernd Fritzsch,et al.  Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. , 2003, Developmental cell.

[85]  J. Rosenstein,et al.  VEGF mRNA and Its Receptorflt-1Are Expressed in Reactive Astrocytes Following Neural Grafting and Tumor Cell Implantation in the Adult CNS , 1998, Experimental Neurology.

[86]  J. LaManna,et al.  Vascular endothelial growth factor in Alzheimer's disease and experimental cerebral ischemia. , 1998, Brain research. Molecular brain research.