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