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Animal models of preeclampsia: investigating pathophysiology and therapeutic targets - PubMed

Review

Animal models of preeclampsia: investigating pathophysiology and therapeutic targets

Bhavisha A Bakrania et al. Am J Obstet Gynecol. 2022 Feb.

Abstract

Animal models have been critical in investigating the pathogenesis, mediators, and even therapeutic options for a number of diseases, including preeclampsia. Preeclampsia is the leading cause of maternal and fetal morbidity and mortality worldwide. The placenta is thought to play a central role in the pathogenesis of this disease because it releases antiangiogenic and proinflammatory factors into the maternal circulation, resulting in the maternal syndrome. Despite the deleterious effects preeclampsia has been shown to have on the mother and baby during pregnancy and postpartum, there is still no effective treatment for this disease. Although clinical studies in patients are crucial to identify the involvement of pathogenic factors in preeclampsia, there are obvious limitations that prevent detailed investigation of the quantitative importance of time-dependent mechanisms involved in this syndrome. Animal models allow investigators to perform proof-of-concept studies and examine whether certain factors found in women with preeclampsia mediate hypertension and other manifestations of this disease. In this brief review, we summarize some of the more widely studied models used to investigate pathophysiological mechanisms that are thought to be involved in preeclampsia. These include models of placental ischemia, angiogenic imbalance, and maternal immune activation. Infusion of preeclampsia-related factors into animals has been widely studied to understand the specific mediators of this disease. These models have been included, in addition to a number of genetic models involved in overexpression of the renin-angiotensin system, complement activation, and trophoblast differentiation. Together, these models cover multiple mechanisms of preeclampsia from trophoblast dysfunction and impaired placental vascularization to the excess circulating placental factors and clinical manifestation of this disease. Most animal studies have been performed in rats and mice; however, we have also incorporated nonhuman primate models in this review. Preclinical animal models not only have been instrumental in understanding the pathophysiology of preeclampsia but also continue to be important tools in the search for novel therapeutic options for the treatment of this disease.

Keywords: animal models; hypertension; preeclampsia.

Copyright © 2020 Elsevier Inc. All rights reserved.

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Figures

Figure 1:
Figure 1:

Mean arterial pressure (MAP; A) and proteinuria (B) is shown for rats following administration of an sFlt-1 adenovirus (Ad-sFlt-1) on during pregnancy. Sprague-Dawley rats were injected on gestational day 8/9 of pregnancy and data was collected on gestational day 16/17. Data are presented as mean+SEM. *P<0.05.

Figure 2:
Figure 2:

Mean arterial pressure (MAP) is shown for normal pregnant rats, the reduced uterine perfusion pressure (RUPP) rat model and inhibition of the angiotensin type 1 receptor autoantibody (AT1-AA) in the RUPP rat (with ‘n7AAc’). These data suggest AT1-AA play a role in placental-ischemia induced hypertension. Data are mean+SEM and was retrieved from Cunningham et al. . *P<0.05.

Figure 3:
Figure 3:

Mean arterial pressure (MAP) in animal models of preeclampsia, with and without administration of an endothelin Type A antagonist. Data is shown for studies in the reduced uterine perfusion pressure (RUPP), sFlt-1 infusion, angiotensin type 1 receptor autoantibody (AT1-AA) infusion and tumor necrosis factor-α (TNF-α) infusion models, suggesting endothelial activation may be a common final pathway in the preeclampsia-related hypertesion. Data are mean+SEM. *P<0.05.

Figure 4:
Figure 4:

Circulating levels of sFlt-1 (A), systolic blood pressure (B) and proteinuria (C) in the uteroplacental ischemia (UPI) non-human primate model of preeclampsia, following a single dose of human siRNA that silence 3 sFlt-1 isoforms (hsiRNAsFLT1-2283/2519). These 3 isoforms are responsible for placental overexpression of sFlt-1 but do not reduce full-length Flt-1 mRNA. Data are mean+SEM. ***P<0.001.

Figure 5:
Figure 5:

Pathways in the pathogenesis of preeclampsia that have been shown and studied in animal models. sFlt-1, solube Flt-1; sEng, soluble endoglin; VEGF, vascular endothelial growth factor; PlGF, placental growth factor; ROS, reactive oxygen species; AT1-AA, angiotensin II Type 1 receptor autoantibody; Th, T helper cell; Tregs, T regulatory cells; IL, interleukin; TNF-α, tumor necrosis factor-α; ET, endothelin; NO, nitric oxide; FGR, fetal growth restriction.

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References

    1. Rana S, Lemoine E, Granger J, Karumanchi SA. Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circ Res. 2019;124(7):1094–1112. - PubMed
    1. McCarthy FP, Ryan RM, Chappell LC. Prospective biomarkers in preterm preeclampsia: A review. Pregnancy Hypertens. 2018;14:72–78. - PubMed
    1. Phipps EA, Thadhani R, Benzing T, Karumanchi SA. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat Rev Nephrol. 2019;15(5):275–289. - PMC - PubMed
    1. Lekva T, Sugulle M, Moe K, Redman C, Dechend R, Staff AC. Multiplex Analysis of Circulating Maternal Cardiovascular Biomarkers Comparing Preeclampsia Subtypes. Hypertension. 2020:1513–1522. - PubMed
    1. McLeod L How useful is uterine artery Doppler ultrasonography in predicting pre-eclampsia and intrauterine growth restriction? CMAJ. 2008;178(6):727–729. - PMC - PubMed

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