Animal models of preeclampsia: an examination of usefulness and limitations based on the metabolic domino theory

Abstract

Animal models of preeclampsia are widely used to elucidate the underlying pathology and investigate the clinical utility of drugs. Although a large body of data has been generated that supports their usefulness, animal models are not necessarily suitable for all research objectives. A more thorough understanding of advantages and disadvantages of each animal model will facilitate selection of appropriate models for a given study area, thereby enabling researchers to obtain more useful research results. The metabolic domino theory offers an explanation for the time-course of increase in the risk of cardiovascular events due to complex interactions among lifestylerelated diseases, which is likened to the sequential falling of dominoes. This theory provides a valuable perspective for understanding the importance of lifestyle-related diseases, as well as the process leading to the onset of cardiovascular events. Preeclampsia has adverse effects on both pregnant women and their fetuses/infants in the short term, whereas in the long term, it also increases the frequency of cardiovascular events in patients approaching middle and old age. Therefore, from a clinical perspective, preeclampsia is considered similar to lifestyle-related diseases, and its pathology might be better understood in light of the metabolic domino theory; this, in turn, will facilitate the selection of an appropriate animal model. Various models are considered applicable for research aimed at elucidating the pathology of preeclampsia, including antiangiogenic factor overexpression models, reduced uterine perfusion pressure (RUPP) models, and risk-and regulatory-factor knockout models. However, in light of the metabolic domino theory, these models do not accurately replicate the pathology of preeclampsia, and are thus not necessarily appropriate for the investigation of drug utility.

Oxidative Stress in Preeclampsia and Placental Diseases

“…These dysfunctions become either causes or consequences of placental-based diseases, such as IUGR, spontaneous pre-term birth, GDM, and, most importantly, PE. In a recent perspective, Seki presented PE symptoms as a series of dominos in varying hierarchical positions [ 161 ]. In the cascade of events leading to eclampsia, HELLP, Premature Birth, or other consequences for the mother and child, placental OS is placed in a very high position, just below placental ischemia due to defective spiral artery remodeling caused by immune maladaptation.…”

Altered offspring neurodevelopment in an L-NAME-induced preeclampsia rat model

“…Therefore, some individuals may consider it a model of gestational hypertension rather than a PE model. Although numerous PE animal models have been established, such as the adenovirus sFlt-1 model, angiotensin II-induced model, and reduced uterine perfusion pressure model, none perfectly mimic all the key features of PE ( 61 ). Finally, we evaluated the neurological characteristics of only male, not female, offspring, to omit the sex-differential effect and the effect of the estrous cycle on behavioral experiments ( 62 , 63 ).…”