Development of an adverse outcome pathway for deposition of energy leading to vascular remodeling

Cardiovascular diseases (CVDs) are complex, encompassing many types of heart pathophysiologies and associated etiologies. It has been shown that fractionated radiation exposure at high doses (3-17 Gy) to the heart increases the incidence of CVD, as evident from radiotherapy studies. However, the effects of low doses of radiation on the cardiovascular system or the effects from space travel, where radiation and microgravity are important contributors to damage, are not clearly understood. Herein, the adverse outcome pathway (AOP) framework was applied to develop an AOP to vascular remodeling from the deposition of energy. Following the creation of a preliminary pathway with the guidance of field experts and authoritative reviews, a scoping review was conducted which informed final key event (KE) selection and facilitated evaluation Bradford Hill criteria of the key event relationships (KERs). The AOP begins with a molecular initiating event of deposition of energy; ionization events increase oxidative stress, which concurrently causes the release of pro-inflammatory mediators and alters signaling pathways. These KEs alter nitric oxide levels leading to endothelial dysfunction and subsequent vascular remodeling (the adverse outcome). The work identifies evidence needed to strengthen understanding of the causal associations for the KERs, emphasizing where there are knowledge gaps and uncertainties in both qualitative and quantitative understanding. The AOP is anticipated to direct future research to better understand the effects of space on the human body and potentially develop countermeasures to better protect future space travelers.