Preeclampsia is a multisystem disorder that remains a major cause of maternal and fetal morbidity and mortality. Yet, no preventive measures are known to preclude the occurrence of the disease. Free radical damage and several metabolic derangement have been implicated in the pathophysiology of this condition (Rodrigo et al., 2005). This study aimed to evaluate the role of oxidative stress, dyslipidemia and markers of tissue damage as indicators of pathogenesis and risk of preeclampsia in pregnant Sudanese women.
In the present study the ages of the two study groups were not statistically different, while the body mass index was significantly higher in preeclamptic women than control group.
Pregnancy is associated with physiologic hyperlipidemia, and in normal pregnancy this feature is not atherogenic, and attributed to hormonal changes (Winkler et al., 2003). Pregnancy-related disorders such as PE are associated with a dysregulation of lipid metabolism manifesting in adverse maternal blood lipid levels (Xiao et al., 2013, Enquobahrie et al., 2004); in consistency, the present study showed marked increased levels of TC, TG and LDL in preeclamptic women than controls, while preeclamptic women revealed significant decrease in HDL level as compared to controls.
These findings agree with other studies. It was reported that there was a significant increase in TC, LDL and TG with significant decrease in HDL in preeclamptic group compared to normotensive group and stated that dyslipidemia plays an important role in the pathogenesis of PE (Vani et al., 2015, Enaruna et al., 2014, Singh et al., 2013, Shalini and Rashmi, 2011, Pradnya and Mona, 2012, Gohil et al., 2011).
The mechanisms underlying dyslipidemia in PE are implicit. One possibility; inconsequential gestational insulin resistance in PE probably increases the mobilization of fatty acid from visceral adipocytes, leading to over production of VLDL by the liver, and suppresses the activity of lipoprotein lipase, culminating in elevated serum TG concentration and reduced serum HDL level which is major risk factor for vascular dysfunction in PE (Gratacos et al., 2003). Alternatively, PE is a state of hypoestrogenemia, which leads to decreased expression of VLDL/apo E receptors resulting in reduced transport of VLDL to fetal compartment and therefore occurrence of maternal hypertriglyceridemia (Leeman and Fontaine, 2008, Aleksandrov et al., 2008). Further LDL taken up by the fetus is decreased due to reduced fetoplacental perfusion leading to increased LDL (Seed et al., 2011). The elevated TG result in increased atherogenic small dense LDL and reduced HDL levels (Romundstad et al., 2010). For the dyslipidemia and PE association, two mechanisms are suggested: firstly, dyslipidemia may induce endothelial dysfunction secondary to oxidative stress and hence occurrence of PE (Ehrenthal et al., 2011). Secondly, dyslipidemia may impair trophoblast invasion by the deposition in predisposed vessels, such as the uterine spiral arteries and contributes to the endothelial dysfunction, therefore to a cascade of pathophysiological events of the development of PE (Chanchal et al., 2015). Lipid excess and oxidative stress can provoke endothelial dysfunction. Alterations of the endothelial dysfunction may underlie the hypertension of PE (Karumanchi et al., 2005). In Examination of the placental transcriptome, recognized pathways affected by inflammation, lipotoxicity, and oxidative stress were amplified significantly in placenta from obese women. Besides, RNA-seq analysis recognized pronounced decrease in genes related to angiogenesis and hormone activity, indicating that maternal dyslipidemia can negatively influence mitochondria leading to increased ROS production, oxidative stress and cellular dysfunction (Saben et al., 2014). Oxidatively stressed placenta releases a number of trophoblast-derived antiangiogenic (e.g., soluble fms-like tyrosine kinase-1, soluble vascular endothelial growth factor, and soluble endoglin), and proangiogenic (e.g., placenta growth factor) factors that contribute to an exaggerated maternal inflammatory response with generalized endothelial dysfunction (Staff et al., 2013). The total cholesterol/high-density lipoprotein ratio (TC/HDL) and the LDL/HDL ratio are two important components and indicators of vascular risk. Interestingly, in this study 32.43% of preeclamptic patients at atherogenic risk (T/HDL)> 4.5; and 35.13% of patients are defined with high-risk when LDL/HDL> 3.0 threshold was applied.
PE is characterized by disturbed extravillous trophoblast migration toward uterine spiral arteries leading to increased uteroplacental vascular resistance and by vascular dysfunction resulting in reduced systemic vasodilatory properties. Its pathogenesis is mediated by an altered bioavailability of NO and tissue damage caused by increased levels of ROS (Matsubara et al., 2015). Vascular function modulated by the interference of ROS and NO. Increased ROS production seems to suppress the expression and function of endothelial NO synthase (Boger et al., 2010).
NO exhibits multiple and complex biological functions and many of its effects can be mostly attributed to its strong oxidant capacity. Thus, NO is an important mediator of immune homeostasis and host defense, and changes in its generation or action can contribute to pathologic states (Wander and Jean, 2010).
In this study, maternal serum NO levels were significantly low in the preeclamptic women compared to controls. NO was negatively and significantly correlated with SBP, DBP, TC, LDL, TG, LDH, AST, and CK, While, HDL and TAC showed positive and significant correlation. Several reports ascertain the decreased levels of NO in PE, and its negative correlation with body weight, systolic blood pressure and diastolic blood pressure (Ehsanipoor et al., 2013, Sharma et al., 2011, Saha et al., 2013, Tayal et al., 2014). In contrast, Norris et al. (1999) reported that the production of NO was significantly higher in the uteroplacental, feto-placental, and peripheral circulation in PE compared to normotensive pregnancies. They attributed the marked increase in NO levels to compensatory mechanism to the pathological effect of PE (Norris et al., 1999).
In normal pregnancy, NO derived from endothelial nitric oxide synthase (eNOS) contributes to the maintenance of vascular tone to increase uterine blood flow (Moncada and Higgs, 2006). An up-regulation of eNOS, resulting in increased NO production has been shown to contribute to increases in uteroplacental blood flow via changes in vascular tone (Sandrim et al., 2008). In addition, there is evidence that genetic eNOS polymorphisms may affect the susceptibility to hypertensive disorders of pregnancy (Sandrim et al., 2010). A study on 3 polymorphisms of the eNOS gene and the plasma nitric oxide concentrations was conducted in a population of Chinese origin from mainland China. Two variants 298Asp allele and eNOS 4a were strongly associated with higher plasma NO concentrations in pregnant women and suggested to modulate PE susceptibility (Chen et al., 2014).Vascular tone is altered by the interference of ROS and NO, increased ROS production seems to suppress the expression of eNOS and hence reduced production of NO (Farrow et al., 2008). In fact, several studies have shown that impaired vascular relaxation in PE has been attributed to reduced bioavailability of NO produced via endothelial NOS (Eleuterio et al., 2013). A reduction in the bioavailability of NO and the imbalance between ROS and antioxidant activity seem to play a critical role in endothelial dysfunction contributing to raised in blood pressure and hence pathogenesis of PE (Sankaralingam et al., 2010, Alpoim et al., 2013). NO is also a potent inhibitor of platelet aggregation and activation by both cGMP-dependent and -independent mechanisms (Crane et al., 2005). Drugs that target various components of the nitric oxide soluble guanylylcyclase pathway can help to increase NO bioavailability, and the delivery of exogenous NO is an attractive therapeutic option (Johal et al., 2014).
Total antioxidant capacity (TAC) parameter summarizes the overall activity of antioxidants and antioxidant enzymes (Prior et al., 2005). Evaluating oxidative stress by measuring TAC can lead to a better understanding of free radical damage in oxidative stress related diseases like PE which would be useful to identify the patients with increased risk of progression of the disease and also for monitoring and optimization of antioxidant therapy (Suresh and Annam, 2013). In our study, the serum level of TAC was statistically low in the preeclamptic patients compared to controls. TAC was negatively correlated with SBP, DBP, BMI, TC, LDL and LDH, while it was positively correlated with HDL and NO. Risk estimate considering antioxidants revealed that pregnant women that have low level of NO and TAC had 7.6 and 2.6 times higher risk to develop oxidative stress which in turn leads to development of PE. Study findings are in agreement with the study of Hasan and Dina (2014) who reported that the serum level of TAC was significantly low in preeclamptic cases signifying that the decrease in TAC leads to an imbalance between prooxidants and antioxidants in those women that go on to develop PE(Hasan and Dina, 2014). Oxidative stress reflects an imbalance between the formation of oxidative substances and the innate antioxidants that make up the endogenous defense system (Buonocore et al., 2010). During normal pregnancy there is a slight increase in oxidative stress, even in the presence of antioxidant systems (Raijmakers et al., 2001). In PE, the Abnormal vascular development of the blood vessels in the placenta leads to reduced placental perfusion and induce hypoxia which is by itself a potent stimulus for ROS formation (Rodrigo et al., 2005).
A genome-wide transcriptomic view identified genes involved in lipid metabolism, angiogenesis, hormone activity, and inflammation to be significantly altered in placenta from obese women. These studies provide evidence for increased lipids and decreased TAC in placenta from obese women, and pinpointed key signaling pathways (increased JNK/FoxO4 signaling) and downstream mediators (HIF-1? and VEGF-A) that provide a link between maternal-obesity, placental inflammation/oxidative stress, and altered angiogenic factors. Obesity provokes cellular stress, which may in turn adversely affect placental development and function(Saben et al., 2014). Antioxidants may be utilized to greater extent to counteract and scavenging free radicals, resulting in the reduction of their levels (Manisha et al., 2015).
The limitations of this study include the relatively small sample size. There were no follow up criteria set. Even with this limitation, the findings of this study serve as ground for further studies to better understanding the associations of total antioxidant capacity and nitric oxide levels with preeclampsia.