Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury (original) (raw)

Vascular and neuronal effects of VEGF in the nervous system: implications for neurological disorders

Seminars in Cell & Developmental Biology, 2002

Vascular endothelial growth factor (VEGF) was originally discovered as an endothelial-specific growth factor. While the predominant role of this growth factor in the formation of new blood vessels (angiogenesis) is unquestioned, recent observations indicate that VEGF also has direct effects on neurons and glial cells, and stimulates their growth, survival and axonal outgrowth. Because of these pleiotropic effects, VEGF has now been implicated in several neurological disorders both in the preterm infant (leukomalacia) and the adult (stroke, neurodegeneration, cerebral and spinal trauma, ischemic and diabetic neuropathy, nerve regeneration). A challenge for the future is to unravel to what extent the effect of VEGF in these disorders relates to its angiogenic activity or direct neurotrophic effect.

Vascular endothelial growth factor and the nervous system

Neuropathology and Applied Neurobiology, 2004

Vascular endothelial growth factor and the nervous system Vascular endothelial growth factor (VEGF) is an angiogenic factor essential for the formation of new blood vessels during embryogenesis and in many pathological conditions. A new role for VEGF as a neurotrophic factor has recently emerged. In the developing nervous system, VEGF plays a pivotal role not only in vascularization, but also in neuronal proliferation, and the growth of coordinated vascular and neuronal networks. After injury to the nervous system, activation of VEGF and its receptors may restore blood supply and promote neuronal survival and repair. There is a growing body of evidence that VEGF is essential for motor neurone survival, and that aberrant regulation of VEGF may play a role in the degeneration of neurones in diseases such as amyotrophic lateral sclerosis.

New roles for VEGF in nervous tissue?beyond blood vessels

Experimental Neurology, 2004

Vascular endothelial growth factor (VEGF) is a secreted dimeric polypeptide that until recently has been believed to be a specific mitogen for endothelial cells subserving angiogenesis and permeability in development and after injury. Recent studies have depicted the localization of VEGF and its receptors on neurons and astrocytes and it has been shown to induce neuritic growth and to provide neuroprotection particularly after ischemia or spinal cord injuries. VEGF also shares common receptor signaling with the guidance molecule SEMA3A and thus could have an additional role linking the coordinated patterning of developing vascular and nervous tissue. It is now apparent that VEGF's role in nervous tissue is pleiotropic in nature, and further elucidation of its mechanisms of action may serve as a key substrate in understanding aspects of neural repair and development. D

Repetitive Intrathecal VEGF 165 Treatment Has Limited Therapeutic Effects after Spinal Cord Injury in the Rat

Journal of Neurotrauma, 2010

Neuropathic pain and motor deficits are detrimental consequences of injury to the spinal cord. In experimental settings, numerous neuroprotective agents are being explored for their therapeutic benefits. Vascular endothelial growth factor (VEGF) is an interesting candidate molecule in this respect since it is not only associated with angiogenesis, but also with neuroprotection and neurite growth. Other investigators have reported improved motor outcomes following intraparenchymal VEGF treatment. Here we demonstrate the therapeutic effects of daily intrathecal treatment of the contused thoracic rat spinal cord with the 165-isoform of VEGF during the first week after injury. We show that VEGF treatment resulted in a statistically significant attenuation of mechanical, but not thermal, hypersensitivity of the hindpaws, while motor deficits remained unaffected. Tissue sparing was also unchanged by VEGF treatment. Microglial responses at the lumbar spinal cord, which have been linked with spinal cord injury-induced hypersensitivity, were found to be unaffected by VEGF treatment. We conclude that repetitive intrathecal VEGF delivery has limited therapeutic effects on spinal cord injury outcome.

Activation of Receptor-Mediated Angiogenesis and Signaling Pathways After VEGF Administration in Fetal Rat CNS Explants

Journal of Cerebral Blood Flow & Metabolism, 2003

The angiogenic role of vascular endothelial growth factor (VEGF) receptors, flk-1 and flt-1, and their downstream signaling pathways, MAPK/ERK and PI-3 kinase, were examined in a fetal rat cortical explant model after exposure to exogenous VEGF. Treatment with VEGF resulted in substantial neovascularization characterized by increased vascular flk-1 receptor expression, whereas flt-1 receptor protein expression was absent. The specific role of flk-1 receptors in the angiogenic process was confirmed by the addition of antisense oligonucleotides (AS-ODNs) to flk-1, which blocked angiogenesis, whereas AS-ODNs to flt-1 had no effect. These results were further supported by the finding that specific chemical inhibition of flk-1 receptors caused disruption of the angiogenic response, whereas inhibition of the flt-1 receptors had no effect.

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.

Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain

Neuroscience, 2002

AbstractöThe e¡ects of exogenous vascular endothelial growth factor (VEGF) on angiogenesis, blood^brain barrier permeability and astroglial proliferation in the adult rat CNS in situ were investigated. Recombinant human VEGF 165 (25 or 50 ng/ml) was delivered for up to 1 week using either intracerebral osmotic minipumps or less traumatic subdural gelatin sponge placement. By 3 days, VEGF delivery caused signi¢cantly increased cerebral angiogenesis (25 ng/ml was most e¡ective) in both experimental models when compared to saline controls; VEGF infusion resulted in a 100% increase in an index of vascular proliferation, and gelatin sponge delivery produced a 65% increase. The blood^brain barrier hallmark endothelial glucose transporter-1 was not present in nascent vascular sprouts. Infusion of VEGF produced extensive protein leakage that persisted after saline-induced permeability was mostly resolved, while gelatin sponge administration caused milder barrier dysfunction. Administration of the angiogenic factor had unexpected proliferative e¡ects on astroglia in both models, resulting in an 80^85% increase in mitotically active astroglia when compared to controls. Immunohistochemical results and semi-quantitative reverse transcriptase-polymerase chain reaction indicated that the VEGF receptors £k-1 and £t-1 were up-regulated in response to the infusion trauma; £t-1 was localized to reactive astroglia, while £k-1 was expressed in vascular endothelium but predominantly in neuronal somata and processes adjacent to the delivery site. mRNA for the VEGF 121 , VEGF 165 and VEGF 188 isoforms was also increased after delivery of the recombinant protein.

Acidic FGF induces NGF and its mRNA in the injured neocortex of adult animals

Molecular Brain Research, 1995

Recently we reported that human recombinant acidic fibroblast growth factor (aFGF) is capable of preventing degeneration of nucleus basalis magnocellularis neurons in vivo and inducing growth of astrocytes in vitro. In the present study, the effects of aFGF on the concentration of nerve growth factor (NGF) and its messenger RNA were investigated in the rat cerebral cortex following unilateral conical infarction. Lesioned animals exhibited a significant increase of NGF in the remaining cortex ipsilateral to the lesion. After combining cortical lesion with intracerebroventricular application of aFGF (12 /xg/day for 7 days), we observed an 8-fold increase in the NGF concentration and a marked increase in the level of steady state NGF mRNA relative to controls ipsilaterally, and a less pronounced aFGF effect in the contralateral cerebral cortex. These results support the hypothesis that the neurotrophic effects previously shown for aFGF and basic FGF (bFGF) in neurotrophin-sensitive neurons is mediated by inducing increased production of NGF within the injured central nervous system (CNS) of adult animals.