The present Adverse Outcome Pathway (AOP) outlines the progression from deposition of energy by radiation exposure to abnormal vascular remodeling, a precursor to cardiovascular disease. The initiating event is the deposition of energy in vascular tissues during ionizing radiation exposure, leading to the radiolysis of water and an overproduction of reactive oxygen species. These reactive molecules overwhelm antioxidant defenses, resulting in oxidative stress and damage to DNA and other cellular components. This cellular stress activates a cascade of altered signaling pathways, including increased production of pro-inflammatory mediators. In the vascular endothelium, these disruptions can impair the regulation of nitric oxide, a key molecule for maintaining vascular tone and integrity. Altered nitric oxide levels contribute to endothelial dysfunction, compromising the ability of blood vessels to respond to physiological stimuli. Persistent dysfunction leads to abnormal vascular remodeling characterized by structural changes such as vessel wall thickening, increased stiffness, and reduced capillary density. This AOP has strong biological plausibility, supported by evidence from animal studies, clinical radiotherapy data, and epidemiological cohorts. However, knowledge gaps remain regarding effects at low doses, chronic exposures, and sex-specific responses. This framework is essential for developing radiation protection strategies, especially in medical and spaceflight contexts.
Adverse Outcome Pathway on Deposition of Energy Leading to Abnormal Vascular Remodeling
