HIF-1α/VEGF signaling pathway may play a dual role in secondary pathogenesis of cervical myelopathy

Long, Houqing; Li, Guang-Sheng; Hu, Yong; Wen, Chunyi; Xie, Wen-Han

doi:10.1016/j.mehy.2012.04.006

Cited by 18 publications

(9 citation statements)

References 26 publications

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“…Therefore, other scientists have concluded that hypoxia may be a useful technique for tissue specific gene therapy, as it has reduced side effects and increased efficacy (30). Long et al (31) determined that in hypoxic conditions following SCI, the upregulation of VEGF is consistent with increasing HIF-1α in acute periods, in accordance with the results of the current study. Furthermore, there is a correlation between VEGF expression and angiogenesis (protecting vascular endothelial cells, increasing blood vessel density and improving regional blood flow), neurogenesis (antiapoptosis, neurotrophy and attenuating axonal degradation), and locomotor ability improvement (32,33).…”

Section: Discussionsupporting

confidence: 92%

Effect of hypoxia-inducible factor-1/vascular endothelial growth factor signaling pathway on spinal cord injury in rats

Chen

Liu

Liang

et al. 2017

Experimental and Therapeutic Medicine

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The aim of the present study was to evaluate the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 (HIF-1), and to investigate the role of the HIF-1/VEGF signaling pathway following spinal cord injury (SCI). A total of 90 12-week-old Sprague Dawley rats were randomly divided into the following three groups: Sham group (operation without SCI); control group (SCI without ML228 treatment); and treatment group (SCI receiving ML228 treatment). ML228 was administered as it is an activator of HIF-1α. The control and treatment groups were subjected to spinal cord hemisection and motor activity was evaluated using the Basso, Beattie and Bresnahan (BBB) scoring system. Expression of HIF-1α and VEGF in each injured spinal cord section was assessed using immunohistochemistry. Prior to SCI, there were no significant differences in the BBB score among the three groups (P>0.05). However, one day after the operation, the BBB score of the sham group was significantly higher than that of the other two groups (P<0.05) and the BBB scores of the control and treatment groups did not differ significantly (P>0.05). BBB scores 3 and 7 days following surgery were significantly higher in the sham group than the other two groups (P<0.05) and the BBB scores of the treatment group were significantly higher than those of the control group (P<0.05). The expression of HIF-1α and VEGF proteins in all groups were measured 1, 3 and 7 days after the operation, and it was observed that their expression was higher in the treatment group than in the control group (P<0.05). Therefore, the results of the current study suggest that ML228 may effectively activate the HIF-1α/VEGF signaling pathway to promote the expression of HIF-1α and VEGF proteins within the injured segment of the spinal cord, which promotes neural functional recovery following SCI in rats. Therefore, treatment with ML228 may be developed as a novel therapeutic strategy to treat SCI.

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Section: Discussionsupporting

confidence: 92%

Effect of hypoxia-inducible factor-1/vascular endothelial growth factor signaling pathway on spinal cord injury in rats

Chen

Liu

Liang

et al. 2017

Experimental and Therapeutic Medicine

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“…Pathway analysis revealed that the genes expressed at higher levels in the S group were enriched for terms related to macrophage markers, Toll-like receptor (TLR) signaling, and chemokine signaling, which regulate inflammation and gliosis in the injured spinal cord [21]. Furthermore, genes related to prostaglandin synthesis and regulation and to oxidative damage, which suggest ischemia of the compressed spinal cord [22], were upregulated in the S group. On the other hand, Neurogenin-2, which mainly regulates the differentiation of dopaminergic neurons (‘dopaminergic neurogenesis’) [23], was downregulated in the S group.…”

Section: Resultsmentioning

confidence: 99%

Inflammatory cascades mediate synapse elimination in spinal cord compression

Takano

Kawabata

Komaki

et al. 2014

J Neuroinflammation

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BackgroundCervical compressive myelopathy (CCM) is caused by chronic spinal cord compression due to spondylosis, a degenerative disc disease, and ossification of the ligaments. Tip-toe walking Yoshimura (twy) mice are reported to be an ideal animal model for CCM-related neuronal dysfunction, because they develop spontaneous spinal cord compression without any artificial manipulation. Previous histological studies showed that neurons are lost due to apoptosis in CCM, but the mechanism underlying this neurodegeneration was not fully elucidated. The purpose of this study was to investigate the pathophysiology of CCM by evaluating the global gene expression of the compressed spinal cord and comparing the transcriptome analysis with the physical and histological findings in twy mice.MethodsTwenty-week-old twy mice were divided into two groups according to the magnetic resonance imaging (MRI) findings: a severe compression (S) group and a mild compression (M) group. The transcriptome was analyzed by microarray and RT-PCR. The cellular pathophysiology was examined by immunohistological analysis and immuno-electron microscopy. Motor function was assessed by Rotarod treadmill latency and stride-length tests.ResultsSevere cervical calcification caused spinal canal stenosis and low functional capacity in twy mice. The microarray analysis revealed 215 genes that showed significantly different expression levels between the S and the M groups. Pathway analysis revealed that genes expressed at higher levels in the S group were enriched for terms related to the regulation of inflammation in the compressed spinal cord. M1 macrophage-dominant inflammation was present in the S group, and cysteine-rich protein 61 (Cyr61), an inducer of M1 macrophages, was markedly upregulated in these spinal cords. Furthermore, C1q, which initiates the classical complement cascade, was more upregulated in the S group than in the M group. The confocal and electron microscopy observations indicated that classically activated microglia/macrophages had migrated to the compressed spinal cord and eliminated synaptic terminals.ConclusionsWe revealed the detailed pathophysiology of the inflammatory response in an animal model of chronic spinal cord compression. Our findings suggest that complement-mediated synapse elimination is a central mechanism underlying the neurodegeneration in CCM.

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“…In hypoxic condition, the up-regulation of VEGF is consistent with increasing HIF-1α in acute periods. HIF-1α/VEGF signaling pathway is thought to play a dual role following acute spinal cord injury [32] , [33] . In the present study, we found that the HIF-1α 1790G>A influences local expression of VEGF and VEGFR in cervical disc tissues.…”

Section: Discussionmentioning

confidence: 99%

HIF-1α Polymorphism in the Susceptibility of Cervical Spondylotic Myelopathy and Its Outcome after Anterior Cervical Corpectomy and Fusion Treatment

et al. 2014

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BackgroundTo investigate the association between the single nucleotide polymorphism (SNP) of hypoxia-inducible factor1 α (HIF-1α) and the susceptibility to cervical spondylotic myelopathy (CSM) and its outcome after surgical treatment.MethodA total of 230 CSM patients and 284 healthy controls were recruited. All patients received anterior cervical corpectomy and fusion (ACF) and were followed for 12 months. The genotypes for two HIF-1α variants (1772C>T and 1790G>A) were determined.ResultsIn the present study, we found that the HIF-1α polymorphism at 1790G>A significantly affects the susceptibility to CSM and its clinical features, including severity and onset age. In addition, the 1790A>G polymorphism also determines the prognosis of CSM patients after ACF treatment. The GG genotype of 1790G>A polymorphism is associated with a higher risk to develop CSM, higher severity and earlier onset age. More importantly, we found that the 1790G>A polymorphism determines the clinical outcome in CSM patients who underwent ACF treatment.ConclusionOur findings suggest that the HIF-1α 1790G>A polymorphism is associated with the susceptibility to CSM and can be used as predictor for the clinical outcome in CSM patients receiving ACF treatment.

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HIF-1α/VEGF signaling pathway may play a dual role in secondary pathogenesis of cervical myelopathy

Cited by 18 publications

References 26 publications

Effect of hypoxia-inducible factor-1/vascular endothelial growth factor signaling pathway on spinal cord injury in rats

Effect of hypoxia-inducible factor-1/vascular endothelial growth factor signaling pathway on spinal cord injury in rats

Inflammatory cascades mediate synapse elimination in spinal cord compression

HIF-1α Polymorphism in the Susceptibility of Cervical Spondylotic Myelopathy and Its Outcome after Anterior Cervical Corpectomy and Fusion Treatment

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