Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center Integrative Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center Integrative Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Exp Cell Res. 2019 Oct 15;383(2):111503. doi: 10.1016/j.yexcr.2019.111503. Epub 2019 Jul 20.
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 β (TGFβ), 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) rapidly stimulates their migration. Additional exogenous TGFβ (0.4 nM) exposure potentiated this effect and increased Furin expression in a TGFβ type I receptor activin-like kinase 5 (ALK5) - dependent manner (prevented by 10 μM SB431542). Furin inhibition prevented hypoxia-induced EC migration and blocked TGFβ-induced potentiation suggesting existence of a feedback loop. TGFβ and Furin were also critical for hypoxia-induced BBB dysfunction. TGFβ 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 TGFβ. Targeting the Furin or ALK5 pathway may offer novel therapeutic strategies for improving BBB stability and CNS function during disease.
缺氧性血脑屏障（BBB）功能障碍是中枢神经系统疾病的常见特征，但其屏障障碍的机制尚不清楚。本研究探讨了转化生长因子β（TGFβ）在缺氧介导的屏障损伤中的作用，TGFβ 是一种已知能诱导蛋白前体转化酶 Furine 表达的细胞因子。我们发现，脑内皮细胞（ECs）暴露于缺氧（1% O）中会迅速刺激其迁移。额外的外源性 TGFβ（0.4 nM）暴露以 TGFβ Ⅰ型受体激活素样激酶 5（ALK5）依赖的方式增强了这种效应，并增加了 Furine 的表达（通过 10 μM SB431542 预防）。Furine 抑制可防止缺氧诱导的 EC 迁移，并阻断 TGFβ 诱导的增强作用，表明存在反馈回路。TGFβ 和 Furine 对缺氧诱导的 BBB 功能障碍也很关键。TGFβ 处理加剧了缺氧诱导的 BBB 通透性增加，但 ALK5 或 Furine 阻断可逆转损伤诱导的通透性变化。因此，在损伤期间，Furine 通过介导 TGFβ 的作用而损害内皮完整性。靶向 Furine 或 ALK5 途径可能为改善疾病期间 BBB 稳定性和中枢神经系统功能提供新的治疗策略。
