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


Baumann, Julia; Huang, Sheng-Fu; Gassmann, Max; Tsao, Chih-Chieh; Ogunshola, Omolara O (2019). Furin inhibition prevents hypoxic and TGFβ-mediated blood-brain barrier disruption. Experimental Cell Research, 383(2):111503.

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 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% O2) rapidly stimulates their migration. Additional exogenous TGFβ (0.4nM) exposure potentiated this effect and increased Furin expression in a TGFβ type I receptor activin-like kinase 5 (ALK5) - dependent manner (prevented by 10μM 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.

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 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% O2) rapidly stimulates their migration. Additional exogenous TGFβ (0.4nM) exposure potentiated this effect and increased Furin expression in a TGFβ type I receptor activin-like kinase 5 (ALK5) - dependent manner (prevented by 10μM 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
05 Vetsuisse Faculty > Center for Clinical Studies
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Cell Biology
Uncontrolled Keywords:Cell Biology, ALK-5; Barrier permeability; Cell migration; Furin; Primary endothelial cells
Language:English
Date:1 October 2019
Deposited On:26 Aug 2019 16:09
Last Modified:29 Jul 2020 11:03
Publisher:Elsevier
ISSN:0014-4827
OA Status:Green
Publisher DOI:https://doi.org/10.1016/j.yexcr.2019.111503
PubMed ID:31336100
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_170129
  • : Project TitleMetabolic processes at the blood-brain barrier and their role in vascular dysfunction
  • : FunderSNSF
  • : Grant ID31003A_150062
  • : Project TitleCell-specific HIF-1 compromises blood-brain barrier integrity: consequences for stroke outcome

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