Peripheral nerve ischemia: apolipoprotein E deficiency results in impaired functional recovery and reduction of associated intraneural angiogenic response

Pola, Roberto; Gaetani, Eleonora; Flex, Andrea; Aprahamian, Tamar; Proia, Anna; Bosch–Marcé, Marta; Smith, Roy C.; Pola, Paolo

doi:10.1016/s0014-4886(03)00260-7

Cited by 17 publications

(16 citation statements)

References 43 publications

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“…apoE(Ϫ/Ϫ) mice exhibited a reduction of unmyelinated axons within the sciatic nerves (Fullerton et al, 1998), and immunoreactivity with the neuronal marker PGP9.5 was reduced compared with that in wild-type mice (Pola et al, 2003). In agreement with these findings, our results also showed that apoE(Ϫ/Ϫ) mice demonstrate a delayed response to noxious thermal stimuli and that the amount of CGRP-LI-containing nerve fibers was reduced compared with that in wild-type mice.…”

Section: Discussionsupporting

confidence: 89%

“…Previous studies have reported that apoE deficiency results in impaired function of sensory nerves (Fullerton et al, 1998;Pola et al, 2003). apoE(Ϫ/Ϫ) mice exhibited a reduction of unmyelinated axons within the sciatic nerves (Fullerton et al, 1998), and immunoreactivity with the neuronal marker PGP9.5 was reduced compared with that in wild-type mice (Pola et al, 2003).…”

Section: Discussionmentioning

confidence: 88%

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The Akt-Nitric Oxide-cGMP Pathway Contributes to Nerve Growth Factor-Mediated Neurite Outgrowth in Apolipoprotein E Knockout Mice

Hashikawa-Hobara

Hashikawa

Yutani

et al. 2011

J Pharmacol Exp Ther

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Apolipoprotein E (apo)-deficient [apoE(Ϫ/Ϫ)] mice have peripheral sensory nerve defects and a reduced and delayed response to noxious thermal stimuli. However, to date, no report has focused on the influence of apoE deficiency on calcitonin gene-related peptide (CGRP)-containing nerve fiber extensions. We have shown that the density of CGRP-containing nerve fibers decreases in mesenteric arteries of apoE(Ϫ/Ϫ) mice compared with wild-type mice. Here, we investigated whether apoE deficiency is involved in nerve growth factor (NGF)-induced CGRP-containing nerve regeneration using apoE(Ϫ/Ϫ) mice. NGF-mediated CGRP-like immunoreactivity (LI)-neurite outgrowth in apoE(Ϫ/Ϫ) cultured dorsal root ganglia (DRG) cells was significantly lower than that in wild-type cultures. However, the level of NGF receptor mRNA in apoE(Ϫ/Ϫ) DRG cells was similar to that in wild-type mice. To clarify the mechanism of the impaired ability of NGF-mediated neurite outgrowth, we focused on the Akt-nitric oxide (NO)-cGMP pathway. Expression of phosphorylated Akt was significantly reduced in apoE(Ϫ/Ϫ) DRG. The NO donor, sodium nitroprusside or S-nitroso-N-acetylpenicillamine, did not affect NGFmediated neurite outgrowth in apoE(Ϫ/Ϫ) cultured DRG cells. However, 8-bromoguanosine 3Ј,5Ј-cyclic monophosphate sodium salt n-hydrate, a cGMP analog, induced NGF-mediated nerve facilitation similar to wild-type NGF-mediated neurite outgrowth levels. Furthermore, in apoE(Ϫ/Ϫ) DRG, soluble guanylate cyclase expression was significantly lower than that in wild-type DRG. These results suggest that in apoE(Ϫ/Ϫ) mice the Akt-NO-cGMP pathway is impaired, which may be caused by NGF-mediated CGRP-LI-neurite outgrowth defects.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 88%

The Akt-Nitric Oxide-cGMP Pathway Contributes to Nerve Growth Factor-Mediated Neurite Outgrowth in Apolipoprotein E Knockout Mice

Hashikawa-Hobara

Hashikawa

Yutani

et al. 2011

J Pharmacol Exp Ther

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“…Increase in hypoxia [3,19], as in conditions of myocardial ischemia [2,11], stimulates VEGF expression. Brain ischemia [4,10], spinal cord ischemia [5], mechanical injury [20], and sciatic nerve ischemia [17] induce VEGF expression in vascular endothelial cells, glial cells, and neurons. We therefore hypothesized that cauda equina compression induces expression of VEGF in the compressed cauda equina and related dorsal root ganglion (DRG).…”

Section: Introductionmentioning

confidence: 99%

Spinal stenosis: assessment of motor function, VEGF expression and angiogenesis in an experimental model in the rat

et al. 2007

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Reduction of blood flow in compressed nerve roots is considered as one important mechanism of induction of neurogenic intermittent claudication in lumbar spinal canal stenosis. Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, and is increased in expression in hypoxic conditions. The objective of this study was to examine if cauda equina compression affects motor function and induces expression of VEGF and angiogenesis. The cauda equina was compressed by placing a piece of silicone rubber into the L5 epidural space. Walking duration was examined by rota-rod testing. The compressed parts of the cauda equina and L5 dorsal root ganglion (DRG) were removed at 3, 7, 14, or 28 days after surgery, and processed for immunohistochemistry for VEGF and Factor VIII (marker for vascular endothelial cells). Numbers of VEGF-immunoreactive (IR) cells and vascular density were examined. Walking duration was decreased after induction of cauda equina compression. The number of VEGF-IR cells in the cauda equina and DRG was significantly increased at 3, 14, and 28 days after cauda equina compression, compared with sham-operated rats (P < 0.05). Vascular density in the cauda equina was not increased at any of the time points examined. Cauda equina compression decreased walking duration, and induced VEGF expression in nerve roots and DRG.

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“…The link between apoE4 and pathological vascularization has not been well elucidated; however, apoE4 is accepted as a risk factor for atherosclerosis (Altenburg et al, 2007;Knouff et al, 1999;Scuteri et al, 2005). In animal model studies, murine apoE is known to influence pathological vascularization (Couffinhal et al, 1999;Pola et al, 2003). Evidence suggests that mice lacking apoE (ApoE−/−) have impaired angiogenesis, as well as a reduced capacity to upregulate VEGF, a prototypical angiogenic cytokine, in response to ischemic stimuli (Couffinhal et al, 1999;Pola et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…In animal model studies, murine apoE is known to influence pathological vascularization (Couffinhal et al, 1999;Pola et al, 2003). Evidence suggests that mice lacking apoE (ApoE−/−) have impaired angiogenesis, as well as a reduced capacity to upregulate VEGF, a prototypical angiogenic cytokine, in response to ischemic stimuli (Couffinhal et al, 1999;Pola et al, 2003). We are aware of no reports confirming whether or not human apoE3 or apoE4 influences corneal neovascularization following ocular HSV-1 infection.…”

Section: Discussionmentioning

confidence: 99%

Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1

Bhattacharjee

Neumann

Foster

et al. 2008

Experimental Eye Research

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The isoform-specific role of human apolipoprotein E (apoE) has been assessed in a mouse model of ocular herpes. Female, age-matched transgenic mice knocked-in for the human allele apoE3 or apoE4 and their parent C57Bl/6 mice were inoculated corneally with HSV-1 strain KOS. Ocular HSV-1 pathogenesis was monitored through viral replication and clinical progression of stromal opacity and neovascularization by slit-lamp examination. Establishment of latency was determined by analysis of HSV-1 DNA (copy number) by specific real-time PCR in the cornea, trigeminal ganglia (TG), and brain. Representative groups of transgenic mice were sacrificed for the analysis of gene expression of vascular endothelial growth factor (VEGF) by reverse-transcription PCR, and apoE expression by Western blot analysis. At 6 days post-infection (P.I.), the ocular infectious HSV-1 titer was significantly higher (p < 0.05) in apoE4 mice compared with apoE3 and C57Bl/6 mice. Corneal neovascularization in apoE4 mice was significantly higher (p < 0.05) than apoE3 and C57Bl/6 mice. The onset of corneal opacity in apoE4 mice was accelerated during days 9--11 P.I.; however, no significant difference in severity was seen on P.I. days 15 and beyond. At 28 days P.I., infected mice of all genotypes had no significant differences in copy numbers (range 0--15) of HSV-1 DNA in their corneas, indicating that HSV-1 DNA copy numbers in cornea are independent of apoE isoform regulation. At 28 days P.I., both apoE4 and C57Bl/6 mice had a significantly higher (p = 0.001) number of copies of HSV-1 DNA in TG compared with apoE3. ApoE4 mice also had significantly higher (p = 0.001) copies of HSV-1 DNA in their TGs compared with C57Bl/6 mice. In brain, both apoE4 and C57Bl/6 mice had significantly higher numbers (p ≤ 0.03) of copies of HSV-1 DNA compared with apoE3 mice. However, the number of HSV-1 DNA copies in the brain of C57Bl/6 mice was not significantly different than that of apoE4 (p = 0.1). Comparative molecular analysis between apoE3 and apoE4 mice on selected days between 7 and 28 P.I., inclusive, revealed that the corneas of apoE4 mice expressed VEGF. None of the corneas in the apoE3 mice expressed VEGF Corresponding author: James M. Hill, Ph.D., LSU Eye Center, 2020 Gravier Street, Suite B, New Orleans, LA 70112, USA, Telephone: (504) 568 2274, Fax: (504) 568 2385, E-mail: jhill@lsuhsc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Western blot analysis showed proteolytic cleavage of the apoE protein in the corneas of the apoE4 mice. Through days 14 to 28 P.I., a ~29 kDa C-terminal truncated apoE f...

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Peripheral nerve ischemia: apolipoprotein E deficiency results in impaired functional recovery and reduction of associated intraneural angiogenic response

Cited by 17 publications

References 43 publications

The Akt-Nitric Oxide-cGMP Pathway Contributes to Nerve Growth Factor-Mediated Neurite Outgrowth in Apolipoprotein E Knockout Mice

The Akt-Nitric Oxide-cGMP Pathway Contributes to Nerve Growth Factor-Mediated Neurite Outgrowth in Apolipoprotein E Knockout Mice

Spinal stenosis: assessment of motor function, VEGF expression and angiogenesis in an experimental model in the rat

Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1

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