Development of an Adverse Outcome Pathway for the onset of hypertension by oxidative stress-mediated perturbation of endothelial nitric oxide bioavailability

Hypertension is a cardiovascular risk factor that has a profound influence on cardiovascular morbidity and mortality. While good progress has been made in terms of identifying and managing this risk factor for patient care, methods to assess the potential of chemical compounds to induce hypertension or to assess the efficacy of consumer products (e.g., e-cigarettes) targeted at reducing disease burden remain largely limited to epidemiological associations and in vivo studies. The field of toxicology has undergone a paradigm shift toward the replacement of in vivo testing in toxicological risk assessment. The adverse outcome pathway (AOP) framework could facilitate improved knowledge-based risk/benefit assessment of chemicals or consumer products, respectively, without the necessity of animal testing. Furthermore, to facilitate a more timely, cost effective, and ethical solution for risk/efficacy assessment purposes, integrated testing strategies are required, which do not heavily rely on in vivo studies. In this study, we present the supporting information on an AOP describing how vascular endothelial peptide oxidation leads to hypertension through perturbation of endothelial nitric oxide bioavailability, leading to impaired vasodilation. We also discuss the essentiality of the key events (KEs), and biological plausibility and empirical support of KE relationships, in accordance with the Organisation for Economic Cooperation and Development (OECD) handbook. This AOP could be a useful tool to serve as a foundation for a future integrated testing strategy for the regulatory assessment of the harm reduction potential of e-cigarettes relative to conventional tobacco products and other consumer products, which aim to reduce cardiovascular disease risk.