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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

Disruption of endothelial barrier integrity by NaCN-treated pericytes involves VEGF.Conditioned media from pericytes treated with NaCN (2mM) increased endothelial barrier permeability, which was ameliorated in HBMECs pretreated with the VEGF-neutralizing antibody. VEGF (100ng/ml)-treated group was used a positive control. All the data are presented as mean±SD of four individual experiments (n = 4). **p<0.01 vs control group; #p<0.05 vs NaCN-treated group.
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pone.0124362.g005: Disruption of endothelial barrier integrity by NaCN-treated pericytes involves VEGF.Conditioned media from pericytes treated with NaCN (2mM) increased endothelial barrier permeability, which was ameliorated in HBMECs pretreated with the VEGF-neutralizing antibody. VEGF (100ng/ml)-treated group was used a positive control. All the data are presented as mean±SD of four individual experiments (n = 4). **p<0.01 vs control group; #p<0.05 vs NaCN-treated group.

Mentions: The fundamental basis for the BBB is the formation of complex tight junctions between adjacent capillary endothelial cells and interaction of pericytes with these cells. In order to assess whether NaCN-exposed pericytes mediated endothelial barrier breach, human brain microvascular endothelial cells (HBMECs) were exposed to conditioned media from pericytes treated with NaCN and assessed for cell permeability. As shown in Fig 5, HBMECs treated with NaCN-exposed pericyte condition media, demonstrated increased barrier permeability. Exposure of HBMECS to NaCN-exposed pericyte conditioned media that was pretreated with VEGF neutralizing antibody failed to demonstrate endothelial barrier breach, thereby implicating the role of VEGF in NaCN-mediated disruption of BBB. In order to further valid the role of VEGF in endothelial barrier damage, HBMECs were treated with VEGF (100ng/ml) alone. As shown in Fig 5, VEGF exposure resulted in increased endothelial cell permeability. However, exposure of HBMECs to NaCN alone failed to affect the integrity of endothelial cells.


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)

Disruption of endothelial barrier integrity by NaCN-treated pericytes involves VEGF.Conditioned media from pericytes treated with NaCN (2mM) increased endothelial barrier permeability, which was ameliorated in HBMECs pretreated with the VEGF-neutralizing antibody. VEGF (100ng/ml)-treated group was used a positive control. All the data are presented as mean±SD of four individual experiments (n = 4). **p<0.01 vs control group; #p<0.05 vs NaCN-treated group.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0124362.g005: Disruption of endothelial barrier integrity by NaCN-treated pericytes involves VEGF.Conditioned media from pericytes treated with NaCN (2mM) increased endothelial barrier permeability, which was ameliorated in HBMECs pretreated with the VEGF-neutralizing antibody. VEGF (100ng/ml)-treated group was used a positive control. All the data are presented as mean±SD of four individual experiments (n = 4). **p<0.01 vs control group; #p<0.05 vs NaCN-treated group.
Mentions: The fundamental basis for the BBB is the formation of complex tight junctions between adjacent capillary endothelial cells and interaction of pericytes with these cells. In order to assess whether NaCN-exposed pericytes mediated endothelial barrier breach, human brain microvascular endothelial cells (HBMECs) were exposed to conditioned media from pericytes treated with NaCN and assessed for cell permeability. As shown in Fig 5, HBMECs treated with NaCN-exposed pericyte condition media, demonstrated increased barrier permeability. Exposure of HBMECS to NaCN-exposed pericyte conditioned media that was pretreated with VEGF neutralizing antibody failed to demonstrate endothelial barrier breach, thereby implicating the role of VEGF in NaCN-mediated disruption of BBB. In order to further valid the role of VEGF in endothelial barrier damage, HBMECs were treated with VEGF (100ng/ml) alone. As shown in Fig 5, VEGF exposure resulted in increased endothelial cell permeability. However, exposure of HBMECs to NaCN alone failed to affect the integrity of endothelial cells.

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