Furin inhibition prevents hypoxic and TGFβ-mediated blood-brain barrier disruption

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 beta (TGF beta), 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% O-2) rapidly stimulates their migration. Additional exogenous TGF beta (0.4 nM) exposure potentiated this effect and increased Furin expression in a TGF beta type I receptor activin-like kinase 5 (ALK5) - dependent manner (prevented by 10 mu M SB431542). Furin inhibition prevented hypoxia-induced EC migration and blocked TGF beta-induced potentiation suggesting existence of a feedback loop. TGF beta and Furin were also critical for hypoxia-induced BBB dysfunction. TGF beta treatment aggravated hypoxia-induced BBB permeability but ALK5 or Ruin blockade reversed injury-induced permeability changes. Thus during insult Furin compromises endothelial integrity by mediating the effects of TGF beta. Targeting the Furin or ALK5 pathway may offer novel therapeutic strategies for improving BBB stability and CNS function during disease.