Lipid-mediated endothelial dysfunction: a common factor to preeclampsia and chronic vascular disease

doi:10.1016/S0301-2115(00)00427-9

European Journal of Obstetrics & Gynecology and Reproductive Biology

Volume 92, Issue 1, September 2000, Pages 63-66

https://doi.org/10.1016/S0301-2115(00)00427-9 Get rights and content

Abstract

Preeclampsia is a complex pathophysiological state where regulatory systems of inflammation and endothelial function are stimulated beyond the physiological limits of normal pregnancy. Different lines of evidence indicate that abnormal lipid metabolism is not a mere manifestation but is also involved in the pathogenesis of the disease. Lipid-mediated oxidative stress is likely to contribute to endothelial hyperstimulation leading to dysfunction and damage. Maternal predisposing factors seem to be essential to explain why some pregnant women develop a systemic syndrome such as preeclampsia and why others do not. Preliminary evidence suggests that abnormal lipid metabolism could be one of these factors. In this review the evidence for the contribution of lipid oxidation in the pathogenesis of preeclampsia, the similarities between preeclampsia and lipid-mediated chronic vascular disease will be summarized, and the reasons to believe that constitutional lipid abnormalities could be one of the maternal predisposing factors for developing the disease will be examined and will be discussed.

Introduction

According to the most recent hypothesis, preeclampsia is a generalised inflammatory state where several plasma factors that regulate endothelial function are altered [1], [2]. Such situation initially provokes an endothelial hyperstimulation that eventually leads to severe endothelial dysfunction [3], resulting in disseminated microangiopathic disease with vasospasm and hypercoagulation. Hypertension and proteinuria are the commonest signs among numerous possible clinical manifestations, such as thrombocytopenia, liver dysfunction, hemolysis and cerebral complications.

Accumulating evidence suggests that lipid peroxides and pro-inflammatory cytokines are major causal factors to induce endothelial dysfunction. Other potential contributors are abnormally increased trophoblastic particles and neutrophil activation [1], which are supposed to act through liberation of peroxides and inflammatory cytokines. Most women with preeclampsia show histological or biochemical evidence of poor placentation, ischemia and pro-inflammatory activity [1], [2], [4]. However, the degree of defective placentation is variable and may not be present in all preeclamptic women, while on the other hand severe placental ischemia does not necessarily lead to preeclampsia [5]. Therefore some other pre-existing maternal factors must be present to result in a preeclamptic syndrome [6]. Those maternal factors are probably alterations associated to the regulation of one or more of the physiological steps altered in preeclampsia and may not always be clinically obvious in the absence of pregnancy [6].

In this review, we will focus on lipid-mediated oxidative stress and lipid metabolism. We will examine how essential they are in the pathogenesis of preeclampsia and how far they could constitute a major predisposing maternal factor for developing the disease.

Section snippets

Evidence for the involvement of lipids in the pathogenesis of preeclampsia

Different lines of evidence indicate that abnormal lipid metabolism is not a mere manifestation of preeclampsia, but that it is directly involved in its pathogenesis. It is known for 20 years that preeclampsia is associated with hypertriglyceridemia [7]. In more recent studies it was reported that triglycerides and free fatty acids are already elevated in the first and second trimester in these women [8], [9]. In vitro experiments have shown an endothelial stimulatory activity of preeclamptic

Common factors in preeclampsia and lipid-mediated chronic vascular disease

Preeclampsia and atherosclerosis share important features. Common epidemiological risk factors are, e.g. diabetes, black race, or hyperhomocysteinemia [6], [36]. In classic studies describing vascular lesions in the placental bed of women with preeclampsia, the term ‘acute atherosis’ was introduced because of the presence of lipid-laden macrophages, or foam-cells, as observed in the atherosclerotic plaque [43]. Atherosclerosis and coronary artery disease (CAD) are both associated with a

Potential contribution of genetically determined lipid abnormalities to predisposition to preeclampsia

It is becoming widely accepted that there are several possible pathogenetic pathways leading to the complex systemic unbalance underlying the preeclamptic syndrome [6]. Even severe degrees of placentation failure can develop without the slightest sign of preeclampsia, and therefore maternal factors must also play an essential role. A variable degree of placental ischemia must be the triggering factor in most cases but in others the pregnant state itself could be sufficient. Over the last years,

Conclusions

Preeclampsia is a complex pathophysiologic state where biological systems involved in the regulation of inflammation and endothelial function are stimulated beyond the physiologic limits of normal pregnancy. Direct and indirect evidence suggest that lipid metabolism is one of the altered systems in preeclampsia, leading to lipid-mediated oxidative stress and endothelial damage. The existence of maternal predisposing factors seems to be essential to explain why some pregnant women develop a

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Free radicals can be generated by many enzymatic processes. These species are extremely reactive and interact with polyunsaturated fatty acids to produce lipid peroxides with a much longer half-life [153–155]. An association of dyslipidemia and the lipid peroxidation product malondialdehyde (MDA) with severity of pregnancy-induced hypertension has been documented.
In recent years, the vascular endothelium has gained attention as a key player in the initiation and development of pregnancy disorders.
Endothelium acts as an endocrine organ that preserves the homeostatic balance by responding to changes in metabolic status. However, in metabolic disorders, endothelial cells adopt a dysfunctional function, losing their normal responsiveness.
During pregnancy, several metabolic changes occur, in which endothelial function decisively participates. Similarly, when pregnancy metabolic disorders occur, endothelial dysfunction plays a key role in pathogenesis.
This review outlines the main findings regarding endothelial dysfunction in three main metabolic pathological conditions observed during pregnancy: gestational diabetes, hypertensive disorders, and obesity and hyperlipidemia. Organ, histological and cellular characteristics were thoroughly described. Also, we focused in discussing the underlying molecular mechanisms involved in the cellular signaling pathways that mediate responses in these pathological conditions.
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There is evidence that oxidative stress occurs prior to the onset of preeclampsia and the placenta is referred as central organ responsible for free radical generation in women with preeclampsia [5]. An excessive increase in biomarkers of oxidative stress and lipid peroxidation has been reported in women with preeclampsia [6]. Increased lipid peroxidation is considered to be a causative pathogenesis factor for preeclampsia [7].
Preeclampsia is a hypertensive disorder in pregnant women, which can be the leading cause of maternal and neonatal death or premature birth. Although the cause of preeclampsia is still not clear, local or systemic oxidative stress may explain the pathological features associated with this complication. However, it is not clear whether oxidative stress is the cause or the result of preeclampsia. For this purpose, the present meta-analysis was intended to evaluate the oxidant and antioxidant status in women with preeclampsia.
Relevant studies were identified after a preliminary investigation of research articles published up to September 2017.
In the overall analysis, including 2953 cases and 3621 controls, a statistically significant reduction in total antioxidant capacity, nitric oxide, superoxide dismutase, glutathione, vitamin E and C was observed in preeclampsia women. On the other hand, a statistically significant increase in malondialdehyde, protein carbonyl, total peroxide, glutathione peroxidase, catalase and uric acid were observed in preeclampsia women. The increased products of oxidative stress, which were found in the present meta-analysis might be an underlying mechanism for endothelial dysfunction in preeclampsia.
This meta-analysis provides a scientific support that primary reduction of antioxidant capacity and increased levels of oxidative stress products may induce a condition in which the pathways responsible for blood pressure homeostasis are disrupted. In conclusion, it is hypothesized when oxidative stress is established, a protective response is induced by increasing some antioxidants. Further studies are warranted to investigate the role of dietary supplementation and genetic variation in women with different ethnicity.
Lipid concentration in small for gestational age (SGA)pregnancies and hypertensive disorders
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An abnormal lipid profile is strongly related to atherosclerotic cardiovascular disease. Furthermore, it has been shown that this type of profile directly causes endothelial dysfunction [1,2]. The most important feature of pregnancy induced hypertension is hypertension via vasospasm in the kidneys, uterus, placenta, and brain.
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In a prospective study, 900 pregnant women between 13 and 23 weeks of pregnancy were studied. Primarily, serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, were measured. Ultimately, the serum lipid levels at 13–23 weeks of pregnancies were compared between the women who later suffered from hypertension disorders or SGA and the matched women with normal pregnancies.
At 13–23 weeks of pregnancy, the mean triglyceride levels were significantly higher in the women who later experienced preeclampsia when compared with normal, matched pregnancies with an appropriate weight for gestational age and women who had gestational hypertension (p = 0.001 and p = 0.014, respectively). Also, triglyceride levels were significantly higher in women with neonates with large for gestational age (LGA) in comparison with those who gave birth to neonates with SGA (p = 0.012) and with uncomplicated matched pregnant women who gave birth to neonates with weight >10th and <90th percentile for their gestational age (p = 0.007).
Only the levels of TG and not any other lipids evaluated were found to be different in pregnancies complicated by preeclampsia when compared to pregnancies complicated by SGA.
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Interaction of these factors with granulocytes may induce the production of superoxide anions (O2−) and related reactive oxygen species (ROS) (Hubel, 1999). Superoxide anions generated by activated granulocytes may initiate oxidative stress, lipid peroxidation and endothelial cell lysis (Gratacós, 2000). Studies on O2− production by granulocytes from normal and preeclamptic women have also provided conflicting results.
Data on the respiratory burst activity of granulocytes from healthy and preeclamptic women have remained contradictory. To investigate the role of reactive oxygen species in the etiology of preeclampsia we measured superoxide anion generation by granulocytes from non-pregnant, healthy, and preeclamptic women. We also examined the reciprocal effects of heat-inactivated and non-inactivated plasma on superoxide production. Superoxide generation was measured by ferricytochrome-c reduction. Superoxide production induced by either phorbol-12,13-dibutirate or N-formyl-methionyl-leucyl-phenylalanine was significantly decreased in granulocytes from normal pregnant women compared with non-pregnant and preeclamptic women. The phorbol-12,13-dibutirate-induced superoxide generation by granulocytes from non-pregnant and preeclamptic women was significantly inhibited by plasma from healthy pregnant women. The N-formyl-methionyl-leucyl-phenylalanine-stimulated superoxide production by granulocytes from non-pregnant and preeclamptic women was suppressed only by non-inactivated plasma, not heat-inactivated plasma from healthy pregnant women. Plasma from preeclamptic women did not influence the phorbol-12,13-dibutirate- and N-formyl-methionyl-leucyl-phenylalanine-induced superoxide production by control granulocytes. The phorbol-12,13-dibutirate-induced superoxide generation by granulocytes from healthy pregnant women was significantly increased by the effect of plasma from non-pregnant and preeclamptic women, but when stimulating with N-formyl-methionyl-leucyl-phenylalanine only non-inactivated plasma caused the same enhancement. These data indicate that reduced superoxide generation in normal pregnancy may be caused by maternal immunosuppressive factors present in plasma. The failure to reduce superoxide production in preeclampsia may be partly responsible for the endothelial dysfunction characteristic of that condition.
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Lipid-mediated endothelial dysfunction: a common factor to preeclampsia and chronic vascular disease

Abstract

Introduction

Section snippets

Evidence for the involvement of lipids in the pathogenesis of preeclampsia

Common factors in preeclampsia and lipid-mediated chronic vascular disease

Potential contribution of genetically determined lipid abnormalities to predisposition to preeclampsia

Conclusions

Am. J. Obstet. Gynecol.

Clin. Obstet. Gynaecol.

Am. J. Obstet. Gynecol.

Metabolism

Obstet. Gynecol.

Methods Enzymol.

Am. J. Obstet. Gynecol.

Am. J. Obstet. Gynecol.

Am. J. Obstet. Gynecol.

Am. J. Obstet. Gynecol.

Prostaglandins Leukotrienes Essential Fatty Acids

Am. J. Obstet. Gynecol.

Am. J. Obstet. Gynecol.

Prostaglandins Leukot Essent Fatty Acids

Am. J. Obstet. Gynecol.

Am. J. Cardiol.

Am. J. Med.

Atherosclerosis

Am. J. Med.

The pathophysiology of preeclampsia

Intensive Care Med.

Endothelial dysfunction in preeclampsia

Semin Reprod Endocrinol.

Inadequate maternal vascular response to placentation in pregnancies complicated by preeclampsia and by small for gestational age infants

Br. J. Obstet. Gynaecol.

What is the place of genetics in the pathogenesis of preeclampsia?

Biol. Neonate.

Fasting serum triglycerides are increased before 20 weeks of gestation in women who later develop preeclampsia

Hypertens Pregnancy

Variation in lipid levels during pregnancy in women with different types of hypertension

Acta Obstet. Gynecol. Scand.

Distinc factors in plasma of preeclamptic women increase endothelial nitric oxide and prostacyclin

Hypertension