Furin inhibition prevents hypoxic and TGFß-mediated blood-brain barrier disruption.
Exp Cell Res
; 383(2): 111503, 2019 10 15.
Article
em 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Barreira Hematoencefálica
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Permeabilidade da Membrana Celular
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Fator de Crescimento Transformador beta
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Furina
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Inibidores Enzimáticos
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Receptor do Fator de Crescimento Transformador beta Tipo I
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Hipóxia
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article