Animal models for Preeclampsia and Preterm Birth
Expiremental animal models have facilitated the development of mechanistic investigations into human reproductive diseases without the numerous ethical and physical problems associated with the use of human tissues/models. The use of animal models for the modelling of two pregnancy-related complications, preeclampsia (PE) and pretrerm birth (PB) have provided valuable insights into the mechanism and/or potential interventions for these related onditions. The variety of models for these conditions will be assessed throughout this paper. Assessment will focus on the ability of the models to mimic the human condition and their effect on the fetus. Continual evaluation of animals models for these related conditions is crucial to a better understanding of their models’ short-falls and the extent to which their use can inform our understanding of PE and PB (McCarthy et al., 2011).
PE is a hypertensive condition which results in approximately 2–8% of pregnancies showing signs of endothelial dysfunction, excess protein in urine and high blood pressure (McCarthy et al., 2011)., PE arises along with the other hypertensive disorders of pregnancy, making it a leading contributor to maternal mortality (Steegers et al., 2010). PE is responsible for one-quarter of neonatal and stillbirths in developing countries (Duley, 2009). In many studies, disturbed placental function in early pregnancy such as impaired trophoblast invasion (McCarthy et al., 2011) has been speculated to cause PE. However, the pathogenesis of PE is still unknown (Steegers et al., 2010). Potentially, another cause of PE could be an Angiogenesis imbalance excess of syncytiotrophoblastderived antiangiogenic factors such as sFlt-1, which is a receptor for vascular endothelial growth factor (VEGF) leading to endothelial dysfunction (Steegers et al., 2010). When exposed to PE, women and children have been shown to have later onset outcomes (Duley, 2009) (what?). PE predisposes mothers to an increased risk of developing hypertension, stroke and ischemic heart disease later in adult life (Duley, 2009). Children of mothers with PE have been shown to have an increased risk of cerebral palsy, hypertension and diabetes or impaired glucose tolerance (Duley, 2009). PE occurs during the early stages of pregnancy, experiments on viable humans would not only be questionable due to limited participants, but it would also have detrimental short and long-term effects on both the mother and child.
PB is the other condition which uses animal models. It occurs when infants are born prematurely at less than 37 weeks’ gestational age (Goldenberg et al., 2008) and is one of the leading contributors of infant mortality in the USA (Ratajczak et al., 2010). This is possibly due to the nature of the spontaneous labour, premature rupture of the membranes (PPROM), and through induced labour or caesarean delivery for maternal or fetal health risk reasons (Goldenberg et al., 2008). There are many contributing factors to preterm birth, including PE or eclampsia, and intrauterine growth restriction (IUGR) as well as risk factors such as infection or inflammation, stress and other immunologically mediated processes (Goldenberg et al., 2008). It is necessary to use animal models in studies for preterm birth, especially with animals such as sheep and mice as they have shorter gestation periods, allowing a greater volume of data to be collected and are the most notable animals used for researching preterm birth. Using an animal model in the research of PB will limit the risks of long term health effects in PB human infants. Infants born small for gestational age are usually caused by PE, with one-fifth of those due to preterm birth (Duley, 2009). This is because delivery is the only known relative cure for PE (Sibai, 2006). Due to the correlations between PE and PB, animal models are essential in further research of other treatments, particularly in PE to avoid using PB as the only treatment.
RUPP Model
Reduced uterine blood flow, secondary to abnormal placental trophoblast invasion, could be a possible cause of PE. Using a model which mimics the reduced uterine blood flow typical of the condition could be an alternative model for the study of PE (Li et al., 2012). This procedure is known as the ‘reduced uterine perfusion pressure’ (RUPP) model and involves surgical constriction of the aorta above the iliac bifurcation and left and right uterine arcade at the ovarian arteries (Fushima et al., 2016). Many different animal species including dogs, sheep and rabbits are used in the RUPP model. However, successfully it has been noted that the model works best in rats (Li et al., 2012). Using rats mimics many of the physiological effects on women diagnosed with PE with the RUPP model (Li et al., 2012); the model mirrors the hypertension, proteinuria, impaired renal function and increases in leptin and blood lactate observed in the human condition (Li et al., 2012). Another outcome shown in the RUPP model is fetal growth restriction, which is a common result of PE in humans (Fushima et al., 2016). The RUPP model has been useful for the investigation of novel treatments for PE. Further treatments have aslso used the RUPP model for physiological outcomes such as hypertension (Fushima et al., 2016). Moreover, it has consistently been used to model intrauterine growth restriction. (Pennington et al., 2012).
Limitations
This model does not mimic the origins of PE in humans which is the impaired trophoblast invasion, however it does mimic several characteristics of PE in humans. Therefore, the RUPP model limits further investigation into other possible causes of PE, such as trophoblast invasion, early immune mechanisms and vascular remodelling abnormalities (Li et al., 2012). The RUPP model mimics the physiological results of PE in humans, although it does not express the characteristics of severe PE, as RUPP model rats failing to replicate the changes in haemoglobin, platelets or liver function seen in humans with PE (Isler et al., 2003).
Topic sentence.Angiogenesis and permeability of both systemic blood vessels and placental vessels is not possible without a protein called VEGF (McCarthy et al., 2011). VEGF is activated by binding to Flt-1 receptors, however, high levels of sFlt-1have been found in women with preeclampsia (McCarthy et al., 2011). SFlt-1 is an antiangiogenic protein variant of a Flt-1 receptor that acts as an antagonist for VEGF which reduces angiogenesis (McCarthy et al., 2011). Therefore, if excess amounts of soluble FMS like tyrosine kinase are administered in animal models, they will produce similar outcomes as in PE (Sunderland et al., 2011). When excess sFlt-1 is administered within rat and mice models, hypertension, proteinuria, and glomerular endotheliosis were expressed much like the outcomes of PE in humans (Maynard et al., 2003). This makes this a viable animal model to further study PE as it mimics the outcomes similar to humans and allows further investigation into the influence of sFlt-1 on angiogenesis (Maynard et al., 2003), without requiring further manipulation or administration of multipule compounds to get the outcomes of PE (Lu et al., 2007) . This animal model shows that sFlt-1 could be used as an indicator to aid in early detection allowing for early intervention which will then limit the many complications of PB (Maynard et al., 2003). Using an excess sFlt-1 model will also contribute to further studies into other possible PE treatments. Suramin and sEng mRNA are other antiangiogenic proteins which could also be used in this model as they also exhibited the outcomes of PE (Sunderland et al., 2011). Pravastatin is a possible treatment for PE researched through RUPP which was shown to limit the effects of excess sFlt-1 (Kumasawa et al., 2011). Unfortunately, pravastatin is shown to be detrimental to fetal development as some sFlt-1 increase is important for normal pregnancy (Reddy et al., 2009).
Limitations
A limitation for this model is that when treated with sFlt-1, non-pregnant animal models also showed PE outcomes (McCarthy et al., 2011) indicating that this animal model does not explore the possibility of PE being a pregnancy specific condition, possibly due to the difference in placental invasion in rodents. This animal model does not replicate the impaired trophoblast invasion typical of preeclampsia (McCarthy et al., 2011).
Infection-Induced PB
Evidence of intrauterine inflammation and/or infections has been shown in 85% of spontaneous preterm deliveries at less than 28 weeks (Elovitz and Mrinalini, 2004). There has been a demonstrated correlation between intrauterine infections and PB, with intrauterine infections caused by bacteria the leading cause of infection-associated PTB . It is not completely understood how this occurs (Elovitz and Mrinalini, 2004). However,it is believed that in some cases, spontaneous PB is due to the maternal inflammatory response to infections which results in an increase in prostaglandins that will lead to myometrial contractions as well as an increase in metalloproteases and chorioamnion weakening and rupture and cervical ripening (Goldenberg et al., 2000). Fetal stress response to infections is also believed to contribute to preterm birth as they release corticotropin-releasing hormones that then increase adrenal cortisol production and increased prostaglandin (Goldenberg et al., 2000). In order to decrease the rates of/or prevent PB, various antibiotics and pharmacological products that obstruct contractions have been tested but unfortunately these have been unsuccessful (Elovitz and Mrinalini, 2004). Animal models can be used to research any possible correlations between infections and PB and also explore ways in which PB may be prevented (Romero et al., 2006). Infections can mimic those in human pregnancy by administering systemically and locally within the pregnant animal (Elovitz and Mrinalini, 2004). By using a systemic administration, the mechanisms behind PB can be explored. However, this does not allow a complete understanding of the pathways which are activated in PB (Elovitz and Mrinalini, 2004). Some models use localised administration of infectious agents like Escherichia coli, which have been injected through intracervical, intrauterine or intra-amniotic administration. Doing this could potentially more accurately mimic human clinical results (Elovitz and Mrinalini, 2004).
Limitations
Even though this model leads to PB, the infections are administered through injections and not started through the vagina or the cervix like they do in human so it does not mimic the beginning of the infection (Goldenberg et al., 2000). The infection administration model is considered a reliable model as it results in PB. It does not however replicate the pathogenesis of infection during pregnancy. Amniotic fluid from preterm birth in humans has been shown not to contain traces of bacteria from infection (Elovitz and Mrinalini, 2004). It is believed that inflammatory animal models would be much more suitable as inflammation is more likely to be the cause of PB.
PAF inflammation-induced PB
The definition of clinical inflammation is pain, redness, heat swelling and impaired function which shows the effects of inflammatory mediators on local blood vessels and tissues (Romero et al., 2006). It is evident that in animal models, intrauterine inflammation is associated with not only PB but also neural fetal injury (Burd et al., 2012). In a study conducted by Michal A Elovitz et al, platelet-activating factors (PAF) were administered into the uterine lumen in pregnant mice. This led to PB by generating PAF through stimulating multiple signal transduction pathways and activating lipopolysaccharides (Elovitz et al., 2003). The PAF inflammation animal model, offers a greater understanding on signal transduction pathways in inflammation-induced PB which leads to potential therapeutic options in prevention of PB (Elovitz et al., 2003). A study done by Elovitz et al. (2003) indicates that PAF receptor antagonists reduced the likelihood of PB following PAF administration. However, using these results in clinical practice is limited because it has been shown that using an IV infusion of such drugs will cause hypotension in mice. Hypotension is known to negatively affect fetal viability in humans (Elovitz et al., 2003).
Limitations
The PAF model does not consider thrombin, a serine protease, which is another mediator of inflammation, that is vital for blood coagulation and has been shown to play a role in PB (Romero et al., 2006). Another limitation is that this model does not replicate the natural pathogenic inflammatory response as PAF was injected into a localised area, much like the use of infectious agents model (Elovitz et al., 2003). PAF receptors were present in the uterus and cervix , meaning through localised administration of PAF receptor antagonist and excess PAF, this increases the accuracy in the inflammatory areas (Elovitz et al., 2003). However because this PAF model mostly used localised administration, it does not take into consideration the systemic effect on the rest of the body which could be a potential route more suited for this model in future research (Elovitz and Mrinalini, 2004). PAF receptors were noted to be present in the uterus and cervix.
In conclusion, these animal models for PE and PB have been shown to expand further research and knowledge on the underlying conditions in hopes of finding potential positive treatments. While the causes of PE are still completely unknown, these animal models provide insight into hypothesised causes as well as a starting basis for potential treatments (McCarthy et al., 2011). With PB, there is slightly more knowledge on the causes and treatments gained through using infection and inflammatory animal models. Further research in potential treatments such as receptor antagonists could further be explored (Elovitz et al., 2003). Continued research of these conditions is necessary due to the lack of understanding of their causes. Gaining a better knowledge of causes can be used to find more potential treatments. Through findings of different treatments, particularly for PE, there will not only be a decline in rates of PE but also rates in PB as they are interlinked and preterm delivery is the only treatment for PE (Sibai, 2006). The future of research into these conditions needs to be with an animal model that replicates both the causes and the outcomes of PE and PB.
References
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