Inhibiting astrocyte connexin-43 hemichannels blocks radiation-induced vesicular VEGF-A release and blood-brain barrier dysfunction.
astrocyte
blood-barrier
brain
calcium
connexin
ionizing radiation
Journal
Glia
ISSN: 1098-1136
Titre abrégé: Glia
Pays: United States
ID NLM: 8806785
Informations de publication
Date de publication:
01 2024
01 2024
Historique:
revised:
28
07
2023
received:
06
06
2023
accepted:
09
08
2023
medline:
13
11
2023
pubmed:
6
9
2023
entrez:
6
9
2023
Statut:
ppublish
Résumé
Therapeutic brain irradiation with ionizing radiation exerts multiple side effects including barrier leakage that disturbs glial-neuronal functioning and may affect cognition. Astrocytes contribute to barrier leakage by endfeet release of various vasoactive substances acting on capillary endothelial cells forming the barrier. Here, we investigated X-ray effects on astrocytic vesicular transport in mice and determined whether interfering with astrocyte connexins affects radiation-induced barrier leakage. We found that astrocytic VEGF-A-loaded VAMP3 vesicles drastically reorganize starting from 6 h post-irradiation and move in a calcium- and Cx43-dependent manner towards endfeet where VEGF-A is released, provoking barrier leakage. Vesicular transport activation, VEGF-A release and leakage 24 h post-irradiation were all potently inhibited by astrocytic Cx43 KO, Cx43S255/262/279/282A (MK4) mutant mice and TATGap19 inhibition of Cx43 hemichannel opening. Astrocyte VEGF release is a major player in complications of brain irradiation, which can be mitigated by anti-VEGF treatments. Targeting Cx43 hemichannels allows to prevent astrocyte VEGF release at an early stage after brain irradiation.
Substances chimiques
Connexin 43
0
Vascular Endothelial Growth Factor A
0
Connexins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
34-50Informations de copyright
© 2023 The Authors. GLIA published by Wiley Periodicals LLC.
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