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Pericytes contribute to the disruption of the cerebral endothelial barrier via increasing VEGF expression: implications for stroke.

Bai Y, Zhu X, Chao J, Zhang Y, Qian C, Li P, Liu D, Han B, Zhao L, Zhang J, Buch S, Teng G, Hu G, Yao H - PLoS ONE (2015)

Bottom Line: Our findings demonstrated that treatment of human brain microvascular pericytes with sodium cyanide (NaCN) and glucose deprivation resulted in increased expression of vascular endothelial growth factor (VEGF) via the activation of tyrosine kinase Src, with downstream activation of mitogen activated protein kinase and PI3K/Akt pathways and subsequent translocation of NF-κB into the nucleus.Conditioned medium from NaCN-treated pericytes led to increased permeability of endothelial cells, and this effect was significantly inhibited by VEGF-neutralizing antibody.Understanding the regulation of VEGF expression could open new avenues for the development of potential therapeutic targets for stroke and other neurological disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Medical School of Southeast University, Nanjing, China.

ABSTRACT
Disruption of the blood-brain barrier (BBB) integrity occurring during the early onset of stroke is not only a consequence of, but also contributes to the further progression of stroke. Although it has been well documented that brain microvascular endothelial cells and astrocytes play a critical role in the maintenance of BBB integrity, pericytes, sandwiched between endothelial cells and astrocytes, remain poorly studied in the pathogenesis of stroke. Our findings demonstrated that treatment of human brain microvascular pericytes with sodium cyanide (NaCN) and glucose deprivation resulted in increased expression of vascular endothelial growth factor (VEGF) via the activation of tyrosine kinase Src, with downstream activation of mitogen activated protein kinase and PI3K/Akt pathways and subsequent translocation of NF-κB into the nucleus. Conditioned medium from NaCN-treated pericytes led to increased permeability of endothelial cells, and this effect was significantly inhibited by VEGF-neutralizing antibody. The in vivo relevance of these findings was further corroborated in the stroke model of mice wherein the mice, demonstrated disruption of the BBB integrity and concomitant increase in the expression of VEGF in the brain tissue as well as in the isolated microvessel. These findings thus suggest the role of pericyte-derived VEGF in modulating increased permeability of BBB during stroke. Understanding the regulation of VEGF expression could open new avenues for the development of potential therapeutic targets for stroke and other neurological disease.

No MeSH data available.


Related in: MedlinePlus

Schematic of the signaling pathways involved in NaCN-mediated induction of VEGF in primary human pericytes.Exposure of pericytes to NaCN resulted in activation of Src, MAPKs and PI3K/Akt signaling pathways, with the downstream activation of the NF-kB transcription factor leading to enhanced expression of VEGF and subsequent increased permeability of endothelial cells.
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pone.0124362.g007: Schematic of the signaling pathways involved in NaCN-mediated induction of VEGF in primary human pericytes.Exposure of pericytes to NaCN resulted in activation of Src, MAPKs and PI3K/Akt signaling pathways, with the downstream activation of the NF-kB transcription factor leading to enhanced expression of VEGF and subsequent increased permeability of endothelial cells.

Mentions: In conclusion, our findings demonstrate detailed molecular mechanisms underlying increased expression of VEGF mediated by NaCN in primary human pericytes with the involvement of activation of MAPKs and PI3K/Akt and downstream transcription factor NF-kB pathways. The schematic of how pericytes induce VEGF in response to NaCN is summarized in Fig 7. These findings provide insights into the development of potential therapeutic targets for stroke with the role of pericytes in this process.


Pericytes contribute to the disruption of the cerebral endothelial barrier via increasing VEGF expression: implications for stroke.

Bai Y, Zhu X, Chao J, Zhang Y, Qian C, Li P, Liu D, Han B, Zhao L, Zhang J, Buch S, Teng G, Hu G, Yao H - PLoS ONE (2015)

Schematic of the signaling pathways involved in NaCN-mediated induction of VEGF in primary human pericytes.Exposure of pericytes to NaCN resulted in activation of Src, MAPKs and PI3K/Akt signaling pathways, with the downstream activation of the NF-kB transcription factor leading to enhanced expression of VEGF and subsequent increased permeability of endothelial cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401453&req=5

pone.0124362.g007: Schematic of the signaling pathways involved in NaCN-mediated induction of VEGF in primary human pericytes.Exposure of pericytes to NaCN resulted in activation of Src, MAPKs and PI3K/Akt signaling pathways, with the downstream activation of the NF-kB transcription factor leading to enhanced expression of VEGF and subsequent increased permeability of endothelial cells.
Mentions: In conclusion, our findings demonstrate detailed molecular mechanisms underlying increased expression of VEGF mediated by NaCN in primary human pericytes with the involvement of activation of MAPKs and PI3K/Akt and downstream transcription factor NF-kB pathways. The schematic of how pericytes induce VEGF in response to NaCN is summarized in Fig 7. These findings provide insights into the development of potential therapeutic targets for stroke with the role of pericytes in this process.

Bottom Line: Our findings demonstrated that treatment of human brain microvascular pericytes with sodium cyanide (NaCN) and glucose deprivation resulted in increased expression of vascular endothelial growth factor (VEGF) via the activation of tyrosine kinase Src, with downstream activation of mitogen activated protein kinase and PI3K/Akt pathways and subsequent translocation of NF-κB into the nucleus.Conditioned medium from NaCN-treated pericytes led to increased permeability of endothelial cells, and this effect was significantly inhibited by VEGF-neutralizing antibody.Understanding the regulation of VEGF expression could open new avenues for the development of potential therapeutic targets for stroke and other neurological disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Medical School of Southeast University, Nanjing, China.

ABSTRACT
Disruption of the blood-brain barrier (BBB) integrity occurring during the early onset of stroke is not only a consequence of, but also contributes to the further progression of stroke. Although it has been well documented that brain microvascular endothelial cells and astrocytes play a critical role in the maintenance of BBB integrity, pericytes, sandwiched between endothelial cells and astrocytes, remain poorly studied in the pathogenesis of stroke. Our findings demonstrated that treatment of human brain microvascular pericytes with sodium cyanide (NaCN) and glucose deprivation resulted in increased expression of vascular endothelial growth factor (VEGF) via the activation of tyrosine kinase Src, with downstream activation of mitogen activated protein kinase and PI3K/Akt pathways and subsequent translocation of NF-κB into the nucleus. Conditioned medium from NaCN-treated pericytes led to increased permeability of endothelial cells, and this effect was significantly inhibited by VEGF-neutralizing antibody. The in vivo relevance of these findings was further corroborated in the stroke model of mice wherein the mice, demonstrated disruption of the BBB integrity and concomitant increase in the expression of VEGF in the brain tissue as well as in the isolated microvessel. These findings thus suggest the role of pericyte-derived VEGF in modulating increased permeability of BBB during stroke. Understanding the regulation of VEGF expression could open new avenues for the development of potential therapeutic targets for stroke and other neurological disease.

No MeSH data available.


Related in: MedlinePlus