Furin inhibition prevents hypoxic and TGFß-mediated blood-brain barrier disruption.
Exp Cell Res
; 383(2): 111503, 2019 10 15.
Article
en En
| MEDLINE
| ID: mdl-31336100
ABSTRACT
Hypoxic blood-brain barrier (BBB) dysfunction is a common feature of CNS diseases however mechanisms underlying barrier disturbance are still largely unknown. This study investigated the role of transforming growth factor ß (TGFß), a cytokine known to induce expression of the proprotein convertase Furin, in hypoxia-mediated barrier compromise. We show that exposure of brain endothelial cells (ECs) to hypoxia (1% O2) rapidly stimulates their migration. Additional exogenous TGFß (0.4â¯nM) exposure potentiated this effect and increased Furin expression in a TGFß type I receptor activin-like kinase 5 (ALK5) - dependent manner (prevented by 10⯵M SB431542). Furin inhibition prevented hypoxia-induced EC migration and blocked TGFß-induced potentiation suggesting existence of a feedback loop. TGFß and Furin were also critical for hypoxia-induced BBB dysfunction. TGFß treatment aggravated hypoxia-induced BBB permeability but ALK5 or Furin blockade reversed injury-induced permeability changes. Thus during insult Furin compromises endothelial integrity by mediating the effects of TGFß. Targeting the Furin or ALK5 pathway may offer novel therapeutic strategies for improving BBB stability and CNS function during disease.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Barrera Hematoencefálica
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Permeabilidad de la Membrana Celular
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Factor de Crecimiento Transformador beta
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Furina
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Inhibidores Enzimáticos
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Receptor Tipo I de Factor de Crecimiento Transformador beta
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Hipoxia
Límite:
Animals
Idioma:
En
Revista:
Exp Cell Res
Año:
2019
Tipo del documento:
Article
País de afiliación:
Suiza