Local Changes in Vascular Architecture Following Partial Spinal Cord Lesion in the Rat

El, Imperato-Kalmar; Ra, McKinney; Schnell, Lisa; Bp, Rubin; Schwab, ME

doi:10.1006/exnr.1997.6449

Cited by 69 publications

(49 citation statements)

References 25 publications

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“…Interestingly, VEGF immunoreactivity did precede angiogenesis occurring from day 3 after injury. In this study, we also found expression of both VEGF mRNA and protein before the time-point when angiogenesis is reported to take place in response to traumatic CNS injuries (Imperato-Kalmar et al, 1997;Nag et al, 1997). The early finding of VEGF in our model is also interesting from the perspective of the reported early induction of integrin ␣ V ␤ 3 , an essential factor in angiogenesis, after ischemic CNS injuries (Okada et al, 1996), which can be induced by VEGF (Abumiya et al, 1999;Senger et al, 1996).…”

Section: Vegf and Traumatic Brain Injuriessupporting

confidence: 55%

VEGF and VEGF Receptor Expression after Experimental Brain Contusion in Rat

Sköld

Gertten

Sandberg-Nordqvist

et al. 2005

Journal of Neurotrauma

124

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Angiogenesis following traumatic brain injury (TBI) may be of importance not only for post-traumatic reparative processes but also for the development of secondary injuries. Vascular endothelial growth factor (VEGF) is a major regulator of endothelial cell proliferation, angiogenesis, and vascular permeability, though its possible involvement in secondary injuries after TBI is largely unknown. This study was undertaken to analyze the expression of VEGF and the VEGF receptors in experimental brain contusion in rat. Twenty-three adult female Sprague-Dawley rats were subjected to a focal cerebral contusion injury by use of a weight-drop model. Four additional rats underwent craniotomy only. The animals were sacrificed 6 h, or 1, 2, 4, 6, 8, or 16 days post-injury. Expression of VEGF and the VEGF receptors VEGFR1 (Flt-1) and VEGFR2 (Flk-1) were studied by in situ hybridization and immunohistochemistry. VEGF messenger (m)RNA and protein expression were detected in astrocytes, neutrophils, and macrophages in or adjacent to the injury from 1 day after injury, with a peak expression after 4-6 days. Flt-1 and Flk-1 mRNA and protein were detected in vessels adjacent to the lesion from 1 day after injury throughout day 6 after injury. It was also noted that Flt-1/Flk-1 and VEGF-positive vessels often were negative for SMI-71, a marker for vessels in areas with blood-brain barrier (BBB). In conclusion, we have demonstrated that TBI leads to an upregulation of VEGF, Flt-1, and Flk-1 mRNA and protein in and around the lesion. The data provide a foundation for future pharmacological intervention studies focusing on posttraumatic angiogenesis and possible injury repair effects of the VEGF system in TBI.

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Section: Vegf and Traumatic Brain Injuriessupporting

confidence: 55%

VEGF and VEGF Receptor Expression after Experimental Brain Contusion in Rat

Sköld

Gertten

Sandberg-Nordqvist

et al. 2005

Journal of Neurotrauma

124

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“…Moreover if vessels act as a source of neurotrophic factors for axons (6), their disappearance might lead to elimination of active axonal sprouts (29). In our model, the strong down-regulation of vessel density was not explained by cystic cavern formation (15,16) and is more consistent with a programmed sequence of events involving endogenous antiangiogenic factors (30).…”

Section: Discussionmentioning

confidence: 57%

Quantitative analysis by in vivo imaging of the dynamics of vascular and axonal networks in injured mouse spinal cord

Dray

Rougon

Debarbieux

2009

Proc. Natl. Acad. Sci. U.S.A.

160

133

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Understanding the endogenous repair capacity of spinal cord is pivotal to develop strategies to improve it. Here we design a paradigm of spinal cord lesion in the dorsal column using a 2-photon microscopy technique to dynamically and chronically monitor simultaneous changes of vascular and axonal networks in living mice up to 4 months postinjury. High-resolution images showed that early explorative sprouting of surviving injured axons resulted in extensive regrowth until and past the lesion site within 2 months. Blood vessel density was transiently up-regulated and most neurovascular interactions occurred within 2 weeks. Timelapse analysis showed that neovessels exerted a potent growth stimulating action, but no guidance effect on neighboring sprouts, possibly because of their geometry and plasticity. Nevertheless, if reconnection depends on axon sprout density, stimulation of angiogenesis would probably be beneficial to repair. More generally, this imaging approach is showing promise to aid in monitoring brain diseases and the efficacy of potential treatments.angiogenesis ͉ axon regeneration ͉ in vivo 2-photon imaging ͉ spinal cord injury ͉ time lapse S pinal cord injury (SCI) induces dramatic cellular and molecular changes in the neuronal environment resulting overall in impaired axonal regeneration (1-3). Posttraumatic disturbance of blood perfusion is, for example, responsible for secondary damage (3), and reports suggest that stimulation of posttraumatic angiogenesis with vascular endothelial growth factor (VEGF) improves functional recovery of injured rodents (4, 5). Optimizing treatments to target vascularization might then be a valuable therapeutic strategy in the context of SCI, but the finding that VEGF signals on axons in addition to blood vessels (6) challenges the importance of the vascular response in the recovery process.The conclusion of these studies is that the dynamics of the interactions occurring between axons and blood vessels and the influence of vascularization on axon regrowth have to be characterized thoroughly at the single axon level. Investigative tools are scarce, however, and poorly compatible with the determination of kinetics as most of the acquired knowledge comes from histological studies on spinal cord sections sampled from different subjects at different time points. A pioneering in vivo study combining wide-field imaging and the use of transgenic mice with fluorescent spinal cord axons reported observations of individual axons over 1 week after SCI (7). However, only a few axons were sampled per mouse and they were observed for a limited time. We sought to design a more dedicated imaging protocol on the basis of 2-photon microscopy (8, 9) to resolve populations of injured axons in 3 dimensions (3D) in the same mouse and to optimize the method to allow dynamic studies over a period of several months. Dual-color imaging allowed simultaneous visualization of posttraumatic vascular responses and for the first time neurovascular interactions were characterized in vivo at a cellul...

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“…It is likely that tensile stress on the spinal cord driven through avulsion forces damages the spinal cord, leading to vasculature disruption, in a similar way to traumatic spinal cord injury. 88 It is possible that root avulsion could damage the radicular arteries that connect to the posterior and anterior spinal arteries, 89 which may explain the loss of RECA-1 endothelial staining bilaterally after L5 SRA. However, although there was a significant contralateral decrease in staining, this did not correlate with the absence of neuronal loss, absence of pain-like behavior, or lack of locomotor impairment.…”

Section: Discussionmentioning

confidence: 99%

Segmental Spinal Root Avulsion in the Adult Rat: A Model To Study Avulsion Injury Pain

Chew

Murrell

Carlstedt

et al. 2013

Journal of Neurotrauma

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Road traffic accidents are the most common cause of avulsion injury, in which spinal roots are torn from the spinal cord. Patients suffer from a loss of sensorimotor function, intractable spontaneous pain, and border-zone hypersensitivity. The neuropathic pains are particularly difficult to treat because the lack of a well-established animal model of avulsion injury prevents identifying the underlying mechanisms and hinders the development of efficacious drugs. This article describes a hindlimb model of avulsion injury in adult rats where the L5 dorsal and ventral spinal root are unilaterally avulsed (spinal root avulsion [SRA]), leaving the adjacent L4 spinal root intact. SRA produced a significant ipsilateral hypersensitivity to mechanical and thermal stimulation by 5 days compared with sham-operated or naïve rats. This hypersensitivity is maintained for up to 60 days. No autotomy was observed and locomotor deficits were minimal. The hypersensitivity to peripheral stimuli could be temporarily ameliorated by administration of amitriptyline and carbamazepine, drugs that are currently prescribed to avulsion patients. Histological assessment of the L4 ganglion cells revealed no significant alterations in calcitonin gene-related peptide (CGRP), IB4, transient receptor potential cation channel subfamily V member 1 (TrpV1), or N52 staining across groups. Immunohistochemistry of the spinal cord revealed a localized glial response, phagocyte infiltration, and neuronal loss within the ipsilateral avulsed segment. A comparable response from glia and phagocytes was also found in the intact L4 spinal cord, supporting the role for central mechanisms within the L4-5 spinal cord in contributing to the generation of the pain-related behavior. The SRA model provides a platform to investigate possible new pharmacological treatments for avulsion injuries.

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Local Changes in Vascular Architecture Following Partial Spinal Cord Lesion in the Rat

Cited by 69 publications

References 25 publications

VEGF and VEGF Receptor Expression after Experimental Brain Contusion in Rat

VEGF and VEGF Receptor Expression after Experimental Brain Contusion in Rat

Quantitative analysis by in vivo imaging of the dynamics of vascular and axonal networks in injured mouse spinal cord

Segmental Spinal Root Avulsion in the Adult Rat: A Model To Study Avulsion Injury Pain

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