Inhibiting astrocyte connexin‐43 hemichannels blocks radiation‐induced vesicular VEGF‐A release and blood–brain barrier dysfunction

Abstract 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.