Computational Models on Pathological Redox Signalling Driven by Pregnancy: A Review

Abstract

Oxidative stress is associated with a myriad of diseases including pregnancy pathologies with long-term cardiovascular repercussions for both the mother and baby. Aberrant redox signalling coupled with deficient antioxidant defence leads to chronic molecular impairment. Abnormal placentation has been considered the primary source for reactive species; however, placental dysfunction has been deemed secondary to maternal cardiovascular maladaptation in pregnancy. While various therapeutic interventions, aimed at combating deregulated oxidative stress during pregnancy have shown promise in experimental models, they often result as inconclusive or detrimental in clinical trials, warranting the need for further research to identify candidates. The strengths and limitations of current experimental methods in redox research are discussed. Assessment of redox status and oxidative stress in experimental models and in clinical practice remains challenging; the state-of-the-art of computational models in this field is presented in this review, comparing static and dynamic models which provide functional information such as protein-protein interactions, as well as the impact of changes in molecular species on the redox-status of the system, respectively. Enhanced knowledge of redox biology in during pregnancy through computational modelling such as generation of Systems Biology Markup Language model which integrates existing models to a larger network in the context of placenta physiology.

Keywords: antioxidant therapy; cardio-obstetrics; integrative modelling; oxidative stress; preeclampsia; systems biology.

Figure 1

HIF-1α signalling in the trophoblast, during the first trimester. Dashed arrows indicate activation, upright arrow indicates increase, blue arrow indicates transcription, black arrow indicates generation.

Figure 2

Role of Oxidative Stress in Pregnancy Pathologies.

Figure 3

S-nitrosylation mechanisms in the endothelium. (a) eNOS-mediated S-nitrosylation of proteins as PTM. (b) S-nitrosylation negative, reversible, regulation of eNOS activity.

Figure 4

Interventions for Redox imbalance. Nutrition, lifestyle changes, chronotherapy, mitochondrial antioxidant therapy and sildenafil citrate interventions have been proven beneficial or are under investigation. alpha-LA = α-Lipoic Acid; ET = l-Ergothioneine.

Figure 5

Interacting redox-sensitive pathways with existing computational models. The generalized model type is named, including a model reference. Detailed information can be found in Supplementary Material S2.

Figure 6

Redox signalling map grouped according to signalling process. Interacting species are indicated as nodes and their interactions as lines. Interactions can be “inhibition”, “positive influence”, “modulation”, “state transition”, and “transport”. Unclear interactions are visualized as dashed lines. (Green = proteins; bright green = simple molecules; purple = phenotypes; blue = ions).