Rescuing vasculature with intravenous angiopoietin-1 and  v 3 integrin peptide is protective after spinal cord injury

Han, Shu; Arnold, Sheila A.; Sithu, Srinivas D; Mahoney, Edward T.; Geralds, Justin T.; Tran, Phuong B.; Benton, Richard; Maddie, Melissa A.; D’Souza, Stanley E.; Whittemore, Scott R.; Hagg, Theo

doi:10.1093/brain/awq034

Cited by 100 publications

(166 citation statements)

References 78 publications

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“…A study by Zhang and colleagues indicated that virallydelivered Ang-1 given days before ischemic brain injury resulted in reduced vascular leakage and decreased lesion volume (Zhang et al, 2002a). Consistent with a recent article on the therapeutic potential of Ang-1 (Han et al, 2010), our results indicate similar improvements of reduced lesion volume and enhanced functional recovery with Ang-1 treatment.…”

Section: Discussionsupporting

confidence: 91%

“…Thurston and associates showed that systemic Ang-1 production by adenoviral gene delivery resulted in reduced vascular leakage induced by VEGF (Thurston et al, 2000), or inflammatory agents (Thurston et al, 1999). A recent study by Han and colleagues indicated that intravenous delivery of Ang-1 had protective effects after SCI (Han et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Sustained Expression of Vascular Endothelial Growth Factor and Angiopoietin-1 Improves Blood–Spinal Cord Barrier Integrity and Functional Recovery after Spinal Cord Injury

Herrera

Sundberg

Zentilin

et al. 2010

Journal of Neurotrauma

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Spinal cord injury (SCI) results in immediate disruption of the spinal vascular network, triggering an ischemic environment and initiating secondary degeneration. Promoting angiogenesis and vascular stability through the induction of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), respectively, provides a possible therapeutic approach in treating SCI. We examined whether supplementing the injured environment with these two factors, which are significantly reduced following injury, has an effect on lesion size and functional outcome. Sustained delivery of both VEGF 165 and Ang-1 was realized using viral vectors based on the adeno-associated virus (AAV), which were injected directly into the lesion epicenter immediately after injury. Our results indicate that the combined treatment with VEGF and Ang-1 resulted in both reduced hyperintense lesion volume and vascular stabilization, as determined by magnetic resonance imaging (MRI). Western blot analysis indicated that the viral vector expression was maintained into the chronic phase of injury, and that the use of the AAV vectors did not exacerbate infiltration of microglia into the lesion epicenter. The combined treatment with AAV-VEGF and AAV-Ang-1 improved locomotor recovery in the chronic phase of injury. These results indicate that combining angiogenesis with vascular stabilization may have potential therapeutic applications following SCI.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Sustained Expression of Vascular Endothelial Growth Factor and Angiopoietin-1 Improves Blood–Spinal Cord Barrier Integrity and Functional Recovery after Spinal Cord Injury

Herrera

Sundberg

Zentilin

et al. 2010

Journal of Neurotrauma

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“…Relatively few studies in the rodent spinal cord injury field have gone beyond 6 weeks post-injury. We (Han et al, 2010), like others (e.g., Kigerl et al, 2006;Rosenberg et al, 2005,), find inflammatory markers such as CD45 for total leukocytes and CD68 for activated microglia still present at 6 weeks post-injury in rats and mice. In humans, activated microglia/macrophages, as detectable by CD68 immunostaining, are also present for weeks to months following spinal cord injury (Fleming et al, 2006).…”

supporting

confidence: 85%

Anti-Inflammatory Treatments during the Chronic Phase of Spinal Cord Injury Improve Locomotor Function in Adult Mice

Arnold

Hagg²

2011

Journal of Neurotrauma

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Our previous data suggested that ongoing inflammation in the spinal cord 6 weeks following spinal cord injury was detrimental to locomotor function. Others have shown in the acute and sub-acute post-injury phase that microglial/macrophage activation and T regulatory cells are detrimental to recovery. Here, C57BL/6 mice with a moderately severe T9 contusion were injected intravenously daily with minocycline, which reduces microglial/ macrophage activation, or with CD25 antibodies, which reduce T regulatory cell function, starting at 6 weeks after injury. Both anti-inflammatory drugs caused an improvement in hindlimb locomotor function over the 2-week treatment, as measured by the Basso Mouse Scale (BMS). The improvement was functionally important, with mice having problems with coordinated stepping (BMS *6) before treatment to walking essentially normally (BMS > 7) at the end of the treatment. The effects diminished within 1 week after termination of the treatments, suggesting an ongoing and dynamic inflammatory process. The area of white matter or the inflammatory markers CD68 for activated microglia/macrophages and CD45 for leukocytes were not different between the groups. These data suggest that inflammation during the chronic phase following spinal cord injury reduces conduction through the epicenter, possibly by release of cytokines, and is amenable to treatment for improved neurological function.

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“…Studies in animal models of SCI show that microvascular damage and hypoperfusion is associated with increased degeneration after SCI. 8,11,23 Advanced studies with accurate monitoring via surgically implanted ISP monitors in concordance with neurological improvement scores could contribute to a better understanding of optimal MAP goals in ATCCS patients and provide clear protocols on the issue.…”

Section: Discussionmentioning

confidence: 99%

Complications and outcomes of vasopressor usage in acute traumatic central cord syndrome

Readdy

Whetstone

Ferguson

et al. 2015

SPI

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OBJECT The optimal mean arterial pressure (MAP) for spinal cord perfusion after trauma remains unclear. Although there are published data on MAP goals after spinal cord injury (SCI), the specific blood pressure management for acute traumatic central cord syndrome (ATCCS) and the implications of these interventions have yet to be elucidated. Additionally, the complications of specific vasopressors have not been fully explored in this injury condition. METHODS The present study is a retrospective cohort analysis of 34 patients with ATCCS who received any vasopressor to maintain blood pressure above predetermined MAP goals at a single Level 1 trauma center. The collected variables were American Spinal Injury Association (ASIA) grades at admission and discharge, administered vasopressor and associated complications, other interventions and complications, and timing of surgery. The relationship between the 2 most common vasopressors—dopamine and phenylephrine—and complications within the cohort as a whole were explored, and again after stratification by age. RESULTS The mean age of the ATCCS patients was 62 years. Dopamine was the most commonly used primary vasopressor (91% of patients), followed by phenylephrine (65%). Vasopressors were administered to maintain MAP goals fora mean of 101 hours. Neurological status improved by a median of 1 ASIA grade in all patients, regardless of the choice of vasopressor. Sixty-four percent of surgical patients underwent decompression within 24 hours. There was no observed relationship between the timing of surgical intervention and the complication rate. Cardiogenic complications associated with vasopressor usage were notable in 68% of patients who received dopamine and 46% of patients who received phenylephrine. These differences were not statistically significant (OR with dopamine 2.50 [95% CI 0.82–7.78], p = 0.105). However, in the subgroup of patients > 55 years, dopamine produced statistically significant increases in the complication rates when compared with phenylephrine (83% vs 50% for dopamine and phenylephrine, respectively; OR with dopamine 5.0 [95% CI 0.99–25.34], p = 0.044). CONCLUSIONS Vasopressor usage in ATCCS patients is associated with complication rates that are similar to the reported literature for SCI. Dopamine was associated with a higher risk of complications in patients > 55 years. Given the increased incidence of ATCCS in older populations, determination of MAP goals and vasopressor administration should be carefully considered in these patients. While a randomized control trial on this topic may not be practical, a multiinstitutional prospective study for SCI that includes ATCCS patients as a subpopulation would be useful for examining MAP goals in this population.

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Rescuing vasculature with intravenous angiopoietin-1 and v 3 integrin peptide is protective after spinal cord injury

Cited by 100 publications

References 78 publications

Sustained Expression of Vascular Endothelial Growth Factor and Angiopoietin-1 Improves Blood–Spinal Cord Barrier Integrity and Functional Recovery after Spinal Cord Injury

Sustained Expression of Vascular Endothelial Growth Factor and Angiopoietin-1 Improves Blood–Spinal Cord Barrier Integrity and Functional Recovery after Spinal Cord Injury

Anti-Inflammatory Treatments during the Chronic Phase of Spinal Cord Injury Improve Locomotor Function in Adult Mice

Complications and outcomes of vasopressor usage in acute traumatic central cord syndrome

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