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Neuronal and astrocytic interactions modulate brain endothelial properties during metabolic stresses of in vitro cerebral ischemia.

Chaitanya GV, Minagar A, Alexander JS - Cell Commun. Signal (2014)

Bottom Line: Neurovascular and gliovascular interactions significantly affect endothelial phenotype.However, in the present study, we used a 3D co-culture model of brain endothelium with neurons and astrocytes in vitro reflecting an intimate neurovascular and gliovascular interactions in vivo.While the cellular signaling interactions in neurovascular and gliovascular units in vivo are much more complex than the 3D co-culture models in vitro, we were still able to observe several important phenotypical changes in brain endothelial properties by metabolically stressed neurons and astrocytes including changes in barrier, lymphocyte adhesive properties, endothelial cell adhesion molecule expression and in vitro angiogenic potential.

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Affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health-Shreveport, Louisiana 71103, USA. jalexa@lsuhsc.edu.

ABSTRACT
Neurovascular and gliovascular interactions significantly affect endothelial phenotype. Physiologically, brain endothelium attains several of its properties by its intimate association with neurons and astrocytes. However, during cerebrovascular pathologies such as cerebral ischemia, the uncoupling of neurovascular and gliovascular units can result in several phenotypical changes in brain endothelium. The role of neurovascular and gliovascular uncoupling in modulating brain endothelial properties during cerebral ischemia is not clear. Specifically, the roles of metabolic stresses involved in cerebral ischemia, including aglycemia, hypoxia and combined aglycemia and hypoxia (oxygen glucose deprivation and re-oxygenation, OGDR) in modulating neurovascular and gliovascular interactions are not known. The complex intimate interactions in neurovascular and gliovascular units are highly difficult to recapitulate in vitro. However, in the present study, we used a 3D co-culture model of brain endothelium with neurons and astrocytes in vitro reflecting an intimate neurovascular and gliovascular interactions in vivo. While the cellular signaling interactions in neurovascular and gliovascular units in vivo are much more complex than the 3D co-culture models in vitro, we were still able to observe several important phenotypical changes in brain endothelial properties by metabolically stressed neurons and astrocytes including changes in barrier, lymphocyte adhesive properties, endothelial cell adhesion molecule expression and in vitro angiogenic potential.

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Differential effects of metabolic stresses on brain endothelial, neurovascular and gliovascular barriers. A)Brain endothelial barrier. Significant differences were observed between normal and OGDR brain endothelial barrier at 4d. B. Neurovascular barrier. Significant differences between aglycemic, hypoxic and OGDR treated neurovascular barrier was observed from 1d until 5d compared to untreated neurovascular barrier. C. Gliovascular barrier. While no significant differences between untreated and hypoxic gliovascular barrier were observed, aglycemic and OGDR gliovascular barrier was significantly different from untreated from 1d to 3d. D. Comparison of untreated brain endothelial, neurovascular and gliovascular barriers. No significant differences between brain endothelial, neurovascular and gliovascular barriers were observed until 2d. However, neurovascular barrier was significantly lower compared to brain endothelial barrier until 4d and gliovascular barrier was significantly lower until 5d. E. Comparison of aglycemic brain endothelial, neurovascular and gliovascular barriers. No significant differences between aglycemic brain endothelial and neurovascular barriers were observed. However, significant increase in aglycemic gliovascular barrier was observed until 3d. Aglycemic gliovascular barrier was significantly lower at 4d and 5d compared to aglycemic brain endothelial barrier. F. Comparison of Hypoxic brain endothelial, neurovascular and gliovascular barriers. While hypoxic neurovascular barrier was significantly lower than hypoxic brain endothelial barrier from 3d, hypoxic gliovascular barrier was significantly lower from 1d until 5d. G. Comparison of OGDR brain endothelial, neurovascular and gliovascular barriers. Both OGDR neurovascular and gliovascular barriers showed a significant increase compared to OGDR brain endothelial barrier until 3d. However, at 4d OGDR gliovascular barrier was significantly lower compared to OGDR brain endothelial and neurovascular barriers. Repeated measures ANOVA from 0h baseline. Values are expressed in percent baseline at 0h ± SEM. Un-paired t-test was used to check significance between groups at the same time point. # P<0.05 is considered significantly different from respective controls at the same time point.
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Figure 1: Differential effects of metabolic stresses on brain endothelial, neurovascular and gliovascular barriers. A)Brain endothelial barrier. Significant differences were observed between normal and OGDR brain endothelial barrier at 4d. B. Neurovascular barrier. Significant differences between aglycemic, hypoxic and OGDR treated neurovascular barrier was observed from 1d until 5d compared to untreated neurovascular barrier. C. Gliovascular barrier. While no significant differences between untreated and hypoxic gliovascular barrier were observed, aglycemic and OGDR gliovascular barrier was significantly different from untreated from 1d to 3d. D. Comparison of untreated brain endothelial, neurovascular and gliovascular barriers. No significant differences between brain endothelial, neurovascular and gliovascular barriers were observed until 2d. However, neurovascular barrier was significantly lower compared to brain endothelial barrier until 4d and gliovascular barrier was significantly lower until 5d. E. Comparison of aglycemic brain endothelial, neurovascular and gliovascular barriers. No significant differences between aglycemic brain endothelial and neurovascular barriers were observed. However, significant increase in aglycemic gliovascular barrier was observed until 3d. Aglycemic gliovascular barrier was significantly lower at 4d and 5d compared to aglycemic brain endothelial barrier. F. Comparison of Hypoxic brain endothelial, neurovascular and gliovascular barriers. While hypoxic neurovascular barrier was significantly lower than hypoxic brain endothelial barrier from 3d, hypoxic gliovascular barrier was significantly lower from 1d until 5d. G. Comparison of OGDR brain endothelial, neurovascular and gliovascular barriers. Both OGDR neurovascular and gliovascular barriers showed a significant increase compared to OGDR brain endothelial barrier until 3d. However, at 4d OGDR gliovascular barrier was significantly lower compared to OGDR brain endothelial and neurovascular barriers. Repeated measures ANOVA from 0h baseline. Values are expressed in percent baseline at 0h ± SEM. Un-paired t-test was used to check significance between groups at the same time point. # P<0.05 is considered significantly different from respective controls at the same time point.

Mentions: Under normal conditions brain endothelial barrier showed a progressive decline from 0 h baseline time point. Significant differences between normal, aglycemic and OGDR challenged brain endothelial barrier were observed at 4d and 5d. The barrier of normal brain endothelial barrier at 4d was 64.14 ± 1.4% (Figure 1A, Additional file 1: Figure S1A).


Neuronal and astrocytic interactions modulate brain endothelial properties during metabolic stresses of in vitro cerebral ischemia.

Chaitanya GV, Minagar A, Alexander JS - Cell Commun. Signal (2014)

Differential effects of metabolic stresses on brain endothelial, neurovascular and gliovascular barriers. A)Brain endothelial barrier. Significant differences were observed between normal and OGDR brain endothelial barrier at 4d. B. Neurovascular barrier. Significant differences between aglycemic, hypoxic and OGDR treated neurovascular barrier was observed from 1d until 5d compared to untreated neurovascular barrier. C. Gliovascular barrier. While no significant differences between untreated and hypoxic gliovascular barrier were observed, aglycemic and OGDR gliovascular barrier was significantly different from untreated from 1d to 3d. D. Comparison of untreated brain endothelial, neurovascular and gliovascular barriers. No significant differences between brain endothelial, neurovascular and gliovascular barriers were observed until 2d. However, neurovascular barrier was significantly lower compared to brain endothelial barrier until 4d and gliovascular barrier was significantly lower until 5d. E. Comparison of aglycemic brain endothelial, neurovascular and gliovascular barriers. No significant differences between aglycemic brain endothelial and neurovascular barriers were observed. However, significant increase in aglycemic gliovascular barrier was observed until 3d. Aglycemic gliovascular barrier was significantly lower at 4d and 5d compared to aglycemic brain endothelial barrier. F. Comparison of Hypoxic brain endothelial, neurovascular and gliovascular barriers. While hypoxic neurovascular barrier was significantly lower than hypoxic brain endothelial barrier from 3d, hypoxic gliovascular barrier was significantly lower from 1d until 5d. G. Comparison of OGDR brain endothelial, neurovascular and gliovascular barriers. Both OGDR neurovascular and gliovascular barriers showed a significant increase compared to OGDR brain endothelial barrier until 3d. However, at 4d OGDR gliovascular barrier was significantly lower compared to OGDR brain endothelial and neurovascular barriers. Repeated measures ANOVA from 0h baseline. Values are expressed in percent baseline at 0h ± SEM. Un-paired t-test was used to check significance between groups at the same time point. # P<0.05 is considered significantly different from respective controls at the same time point.
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Figure 1: Differential effects of metabolic stresses on brain endothelial, neurovascular and gliovascular barriers. A)Brain endothelial barrier. Significant differences were observed between normal and OGDR brain endothelial barrier at 4d. B. Neurovascular barrier. Significant differences between aglycemic, hypoxic and OGDR treated neurovascular barrier was observed from 1d until 5d compared to untreated neurovascular barrier. C. Gliovascular barrier. While no significant differences between untreated and hypoxic gliovascular barrier were observed, aglycemic and OGDR gliovascular barrier was significantly different from untreated from 1d to 3d. D. Comparison of untreated brain endothelial, neurovascular and gliovascular barriers. No significant differences between brain endothelial, neurovascular and gliovascular barriers were observed until 2d. However, neurovascular barrier was significantly lower compared to brain endothelial barrier until 4d and gliovascular barrier was significantly lower until 5d. E. Comparison of aglycemic brain endothelial, neurovascular and gliovascular barriers. No significant differences between aglycemic brain endothelial and neurovascular barriers were observed. However, significant increase in aglycemic gliovascular barrier was observed until 3d. Aglycemic gliovascular barrier was significantly lower at 4d and 5d compared to aglycemic brain endothelial barrier. F. Comparison of Hypoxic brain endothelial, neurovascular and gliovascular barriers. While hypoxic neurovascular barrier was significantly lower than hypoxic brain endothelial barrier from 3d, hypoxic gliovascular barrier was significantly lower from 1d until 5d. G. Comparison of OGDR brain endothelial, neurovascular and gliovascular barriers. Both OGDR neurovascular and gliovascular barriers showed a significant increase compared to OGDR brain endothelial barrier until 3d. However, at 4d OGDR gliovascular barrier was significantly lower compared to OGDR brain endothelial and neurovascular barriers. Repeated measures ANOVA from 0h baseline. Values are expressed in percent baseline at 0h ± SEM. Un-paired t-test was used to check significance between groups at the same time point. # P<0.05 is considered significantly different from respective controls at the same time point.
Mentions: Under normal conditions brain endothelial barrier showed a progressive decline from 0 h baseline time point. Significant differences between normal, aglycemic and OGDR challenged brain endothelial barrier were observed at 4d and 5d. The barrier of normal brain endothelial barrier at 4d was 64.14 ± 1.4% (Figure 1A, Additional file 1: Figure S1A).

Bottom Line: Neurovascular and gliovascular interactions significantly affect endothelial phenotype.However, in the present study, we used a 3D co-culture model of brain endothelium with neurons and astrocytes in vitro reflecting an intimate neurovascular and gliovascular interactions in vivo.While the cellular signaling interactions in neurovascular and gliovascular units in vivo are much more complex than the 3D co-culture models in vitro, we were still able to observe several important phenotypical changes in brain endothelial properties by metabolically stressed neurons and astrocytes including changes in barrier, lymphocyte adhesive properties, endothelial cell adhesion molecule expression and in vitro angiogenic potential.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health-Shreveport, Louisiana 71103, USA. jalexa@lsuhsc.edu.

ABSTRACT
Neurovascular and gliovascular interactions significantly affect endothelial phenotype. Physiologically, brain endothelium attains several of its properties by its intimate association with neurons and astrocytes. However, during cerebrovascular pathologies such as cerebral ischemia, the uncoupling of neurovascular and gliovascular units can result in several phenotypical changes in brain endothelium. The role of neurovascular and gliovascular uncoupling in modulating brain endothelial properties during cerebral ischemia is not clear. Specifically, the roles of metabolic stresses involved in cerebral ischemia, including aglycemia, hypoxia and combined aglycemia and hypoxia (oxygen glucose deprivation and re-oxygenation, OGDR) in modulating neurovascular and gliovascular interactions are not known. The complex intimate interactions in neurovascular and gliovascular units are highly difficult to recapitulate in vitro. However, in the present study, we used a 3D co-culture model of brain endothelium with neurons and astrocytes in vitro reflecting an intimate neurovascular and gliovascular interactions in vivo. While the cellular signaling interactions in neurovascular and gliovascular units in vivo are much more complex than the 3D co-culture models in vitro, we were still able to observe several important phenotypical changes in brain endothelial properties by metabolically stressed neurons and astrocytes including changes in barrier, lymphocyte adhesive properties, endothelial cell adhesion molecule expression and in vitro angiogenic potential.

Show MeSH
Related in: MedlinePlus