Vascular Pathology as a Potential Therapeutic Target in SCI

Benton, Richard; Hagg, Theo

doi:10.1007/s12975-011-0128-7

Cited by 15 publications

(12 citation statements)

References 182 publications

(242 reference statements)

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“…Indeed, mechanical injury to the spinal cord rapidly damages the spinal microvasculature resulting in acute intraspinal bleeding with progressive hemorrhagic necrosis (PHN), which is highly destructive. In fact, interventions that prevent or reduce PHN after SCI are markedly protective (Noble and Wrathall, 1989a; 1989b; Hill, 2001; Simard et al, 2007; 2010; Benton and Hagg, 2011; Popovich et al, 2011; Simard et al, 2012; 2013). However, bleeding can have conflicting effects on glia, especially oligodendrocyte lineage cells.…”

Section: Introductionmentioning

confidence: 99%

Changes in NG2 cells and oligodendrocytes in a new model of intraspinal hemorrhage

Sahinkaya

Milich

McTigue

2014

Experimental Neurology

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Spinal cord injury (SCI) evokes rapid deleterious and reparative glial reactions. Understanding the triggers for these responses is necessary for designing strategies to maximize repair. This study examined lesion formation and glial responses to vascular disruption and hemorrhage, a prominent feature of acute SCI. The specific role of hemorrhage is difficult to evaluate in trauma-induced lesions, because mechanical injury initiates many downstream responses. To isolate vascular disruption from trauma-induced effects, we created a novel and reproducible model of collagenase-induced intraspinal hemorrhage (ISH) and compared glial reactions between unilateral ISH and a hemi-contusion injury. Similar to contusion injuries, ISH lesions caused loss of myelin and axons and became filled with iron-laden macrophages. We hypothesized that intraspinal hemorrhage would also initiate reparative cellular responses including NG2+ oligodendrocyte progenitor cell (OPC) proliferation and oligodendrocyte genesis. Indeed, ISH induced OPC proliferation within 1d post-injury (dpi), which continued throughout the first week and resulted in a sustained elevation of NG2+ OPCs. ISH also caused oligodendrocyte loss within 4h that was sustained through 3d post-ISH. However, oligodendrogenesis, as determined by bromo-deoxyuridine (BrdU) positive oligodendrocytes, restored oligodendrocyte numbers by 7dpi, revealing that proliferating OPCs differentiated into new oligodendrocytes after ISH. The signaling molecules pERK1/2 and pSTAT3 were robustly increased acutely after ISH, with pSTAT3 being expressed in a portion of OPCs, suggesting that activators of this signaling cascade may initiate OPC responses. Aside from subtle differences in timing of OPC responses, changes in ISH tissue closely mimicked those in hemi-contusion tissue. These results are important for elucidating the contribution of hemorrhage to lesion formation and endogenous cell-mediated repair, and will provide the foundation for future studies geared toward identifying the role of specific blood components on injury and repair mechanisms. This understanding may provide new clinical targets for SCI and other devastating conditions such as intracerebral hemorrhage.

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Section: Introductionmentioning

confidence: 99%

Changes in NG2 cells and oligodendrocytes in a new model of intraspinal hemorrhage

Sahinkaya

Milich

McTigue

2014

Experimental Neurology

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“…[1][2][3][4] Early vasospasm, including that of the pial vessels, causes ischemia in rats and cats as identified by microangiography and hydrogen clearance measurements. [5][6][7] SCI also results in hemorrhage caused by microvascular disturbances and results in secondary hemorrhagic necrosis.…”

Section: Introductionmentioning

confidence: 99%

Intravenous Infusion of Magnesium Chloride Improves Epicenter Blood Flow during the Acute Stage of Contusive Spinal Cord Injury in Rats

Muradov

Hagg

2013

Journal of Neurotrauma

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Vasospasm, hemorrhage, and loss of microvessels at the site of contusive or compressive spinal cord injury lead to infarction and initiate secondary degeneration. Here, we used intravenous injection of endothelial-binding lectin followed by histology to show that the number of perfused microvessels at the injury site is decreased by 80-90% as early as 20 min following a moderate T9 contusion in adult female rats. Hemorrhage within the spinal cord also was maximal at 20 min, consistent with its vasoconstrictive actions in the central nervous system (CNS). Microvascular blood flow recovered to up to 50% of normal volume in the injury penumbra by 6 h, but not at the epicenter. A comparison with an endothelial cell marker suggested that many microvessels fail to be reperfused up to 48 h post-injury. The ischemia was probably caused by vasospasm of vessels penetrating the parenchyma, because repeated Doppler measurements over the spinal cord showed a doubling of total blood flow over the first 12 h. Moreover, intravenous infusion of magnesium chloride, used clinically to treat CNS vasospasm, greatly improved the number of perfused microvessels at 24 and 48 h. The magnesium treatment seemed safe as it did not increase hemorrhage, despite the improved parenchymal blood flow. However, the treatment did not reduce acute microvessel, motor neuron or oligodendrocyte loss, and when infused for 7 days did not affect functional recovery or spared epicenter white matter over a 4 week period. These data suggest that microvascular blood flow can be restored with a clinically relevant treatment following spinal cord injury.

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“…4 Remodeling of spinal cord vasculature has an important role in the process of repair after SCI. 25 Posttraumatic spinal cord angiogenesis is a local metabolic adaptation to improve spinal cord ischemia. Studies have demonstrated temporary angiogenesis in the damaged and surrounding areas of the central nervous system at 3-7 days after trauma, a peak in angiogenesis at 7 days, and a gradual reduction thereafter.…”

Section: Discussionmentioning

confidence: 99%

3D angioarchitecture changes after spinal cord injury in rats using synchrotron radiation phase-contrast tomography

Cao

et al. 2015

Spinal Cord

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Study design: A basic experiment study. Objectives: An understanding of the three-dimensional (3D) angioarchitecture changes that occur after SCI will improve our knowledge of the pathogenesis of SCI and aid in the development of valuable therapeutic strategies to improve its poor outcomes. Our aim was to visualize the normal and traumatized spinal angioarchitecture in 3D using a high-resolution synchrotron radiation phase-contrast tomography (SR-PCT) and evaluate its diagnostic capability. Setting: SCI Center of Xiangya Hospital of Central South University in China. Methods: SR-PCT was used as novel high-resolution imaging tool to detect 3D morphological alterations in spinal cord microvasculature after injury. Results: In a rat model, the morphology of the microvasculature on 2D digital slices was matched with histological findings in both the normal and injured spinal cord. 3D angioarchitecture changes after SCI were successfully obtained via SR-PCT without the use of a contrast agent. Quantitative analysis on 3D images of the injured spinal cord revealed a significant decrease in the number and volume of vascular networks. This was especially relevant to vessels with a diameter o50 μm. Conclusion: The 3D local blood supply to the spinal cord was severely disrupted after the acute violent injury. Our results indicate that the use of SR-PCT may improve our understanding of the pathogenesis of SCI and provide a new approach to the morphological investigation of neurovascular diseases in preclinical research. INTRODUCTIONThe spinal cord microvasculature is a complex and delicate threedimensional (3D) structure in the central nervous system. Under normal physiological conditions, the spinal cord microvasculature enables neural tissue to survive by providing necessary nutrition and maintaining a balanced local microenvironment. 1 Under the pathological process of a spinal cord injury (SCI), acute trauma can severely injure the spinal cord vasculature and result in irreversible damage to neurological function. 2 Revascularization following SCI is a complex process that involves remodeling of the number, connectivity, spatial distribution and direction of blood vessels, all of which affect the functional recovery of the spinal cord from trauma-induced ischemia. 3 Knowledge of the 3D pathologic changes in the spinal cord microvasculature after SCI may aid in the development of valuable therapeutic strategies to improve its poor outcomes. Currently, there is a lack of effective imaging techniques for quantitative evaluation of the microvasculature difference in normal and injured spinal cord models. A number of studies have used 2D and 3D imaging to investigate the vascular response to SCI, but available technology is not sophisticated enough to provide clinically meaningful results. 4 Micro-computed tomography is a powerful 3D imaging tool that is widely used to examine the morphology of various biomedical structures. 5 However, low spatial resolution renders this tool unsuitable for accurate and complete 3D reconst...

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Vascular Pathology as a Potential Therapeutic Target in SCI

Cited by 15 publications

References 182 publications

Changes in NG2 cells and oligodendrocytes in a new model of intraspinal hemorrhage

Changes in NG2 cells and oligodendrocytes in a new model of intraspinal hemorrhage

Intravenous Infusion of Magnesium Chloride Improves Epicenter Blood Flow during the Acute Stage of Contusive Spinal Cord Injury in Rats

3D angioarchitecture changes after spinal cord injury in rats using synchrotron radiation phase-contrast tomography

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