Radiotherapeutic treatment of brain tumors consists of targeted and precise application of radiation beams but exposure of surrounding healthy tissue is inevitable In the brain, ionizing radiation induces breakdown of the blood-brain barrier through its effects on brain microvascular endothelial cells Damage from directly irradiated cells can be transferred to surrounding non-exposed bystander cells, known as the radiation-induced bystander effect to which connexin-based gap junctions and paracrine communication pathways contribute Here, we propose investigations towards the involvement of connexins that facilitate calcium signal expansion at distance by gap junction channels and hemichannels We built on a signaling network, based on reactive oxygen species (ROS), intracellular calcium, inositol trisphosphate (IP3), ATP and nitric oxide (NO) signaling, to understand brain endothelial bystander responses occurring tens of millimeters away from the directly irradiated zone and disturbing blood-brain function, investigated through in vitro and in vivo approaches