WRITE UPS - OBSTETRIC VASCULOPATHY - Reducing Systems In Pre-Eclampsia


The etiology of preeclampsia is still unknown. The 4 hypotheses currently accepted are the placental ischemia hypothesis, genetic hypothesis, the immune maladaption and hypothesis of the imbalance between free oxygen radicals and scavengers in favor of oxidants. At the present is most popular the theory of oxidative stress, that lead to increased production of lipid peroxides, thromboxane A2 and decreased level of prostacyclin. This imbalance triggers endothelial dysfunction and its clinical manifestation. Scavenging reducing systems have protective effect in this process. This chapter reviews these oxidative stress and the current status of reducing systems like Vit. C and E in pre-eclampsia.


 Free Radicals And Reactive Oxygen Species:

A free radical is any molecular species capable of independent, albeit brief, existence that contains one or more unpaired electrons.

There are comprehensive reviews on interactions between reactive oxygen species and reducing systems in human health and disease. Tissue ischemia/hypoxia followed by reperfusion is one established generator of reactive oxygen species and lipid peroxidation in vivo. Postischemic reperfusion generation of reactive oxygen species could be one source of oxidative injury in placentae of women with preeclampsia.

Recently decreased expression of reducing systems thioredoxin and glutaredoxin in placentae from pregnancies with pre-eclampsia and intrauterine growth restriction have been documented. Placental tissue from normal pregnancies (NC), severe pre-eclampsia with fetuses small for gestational age (SPE), mild pre-eclampsia with fetuses small for gestational age (MPE) and pregnancies with small fetuses for gestational age without any sign of pre-eclampsia (IUGR) was collected immediately after delivery. The levels of these proteins were increased approximately 2- to 3-fold in the pre-eclamptic placentae compared to the normal placentae. These results indicated that the pre-eclamptic placentae were exposed to oxidative stress and that the protein thiol/disulphide oxidoreductases were adaptively induced in pre-eclamptic placentae, suggesting possible roles for thioredoxin, glutaredoxin, and protein disulphide isomerase in protecting placental functions against oxidative stress caused by pre-eclampsia.

A diverse array of cellular and extra cellular fluid reducing systems has evolved to control and compartmentalize, but not necessarily eliminate, the production of reactive oxygen species; Reducing systems examined in normal and pre-eclamptic pregnancies include the enzymatic reducing systems (super oxide dismutases (SOD), catalase, and glutathione peroxidase), and transition metal binding proteins (transferrin, ceruloplasmin, and ferritin).

 Lipid Peroxidation:

  Lipid peroxidation has received a great deal of attention in preeclampsia. The primary products of lipid peroxidation, lipid hydroperoxides, function in normal physiology. Reactive oxygen species/ reducing system imbalances can lead to uncontrolled lipid peroxidation.

 Oxidative Stress And The Vascular Endothelium:

 Circulating lipids have diverse effects upon endothelial cell function, and dyslipidemia is associated with endothelial cell dysfunction. Continued oxidation is facilitated (primed) by “ feed-forward” interaction of lipid hydroperoxides in the LDL particle with cell-derived oxidants. Also, the “oxidative stress theory” of preeclampsia finds indirect support in that many of the endothelial abnormalities described in preeclampsia can be reproduced by lipid peroxidation in experimental system.


 Placental Nitrotyrosine, Xanthine Oxidase, And The Issue Of Reperfusion Damage:

Tissue hypoxia/ ischemia followed by reoxygenation can generate reactive oxygen species and lipid peroxidation in vivo. If conjoined with vascular reperfusion, placental hypoxia /ischemia could result in oxidative damage and elaboration of cytotoxic reactive oxygen products into the circulation. However, it is unclear whether placental postischemic reoxygenation damage occurs in preeclampsia.

Placental trophoblasts produce nitric oxide. Preeclampsia and intrauterine growth restriction are associated with increased expression of the endothelial isoform of nitric oxide synthase (eNOS) in the villous vessel endothelium. The role of nitric oxide (NO) in normal pregnancy and pregnancy complicated with preeclampsia (PE) and/or intrauterine growth restriction (IUGR) is under investigations.

 Placental Lipid Peroxidation:

  The lipid peroxidation degradation product, malondialdehyde, is reportedly increased in placental tissue along with decreases in SOD activity in preeclampsia. In pre-eclampsia, increased levels of lipid peroxide and decreased SOD activity have been described in the placenta. Chemical inhibition of placental glutathione peroxides resulted in increased production of lipid hydroperoxides and an increase in the placental thromboxane to prostacyclin output ratio. The consequences of this altered ratio might include vasospasm with exacerbation of placental ischemia, increased cell damage, and increased lipid peroxidation (amplification loop)

The dyslipidemia of preeclampsia is best understood in the context of lipid changes during normal pregnancy.

 Lipid Metabolism In Normal Pregnancy:

Circulating lipids are carried primarily in lipoproteins, which are composed primarily of free and esterified lipids, proteins (apolipoprotein), and phospholipids. The two main cholesterol- carrying lipoproteins are LDL and high-density lipoproteins (HDL). The triglyceride-enrichment of LDL and HDL contributing to hyper- triglyceridemia may be due to increased cholesteryl ester transfer protein (CETP) activity during normal pregnancy.

 Dyslipidemia In Preeclampsia:

Super-normal increases in serum triglyceride and free fatty acids develop as early as 10 weeks’ gestation in women destined to develop preeclampsia. Nearly 50% of women with preeclampsia have triglyceride concentrations > 400 mg/ dL. Total cholesterol 12,14,101 and LDL – cholesterol concentrations are usually not different whereas HDL2 cholesterol is decreased in clinically evident preeclampsia.


Free fatty acid increases might contribute to endothelial dysfunction in preeclampsia by several means. The pathogenic significance of small, dense LDL, and the formation of small, dense LDL, during normal and preeclamptic pregnancy are summarized in the next two sections,

 Small Dense LDL Phenotype And Its Vascular Consequences:

 Metabolic changes producing hypertriglyceridemia generally shift the spectrum of LDL sub fractions toward a proportional increase of smaller, denser LDL. Small, dense LDL particles are relatively depleted of cholesteryl esters, and enriched in protein. Proportional increases in small, dense LDL with heightened susceptibility to oxidative modification may account for part of the increased cardiovascular risk in individuals with the small, dense LDL phenotype. The reasons for increased oxidation susceptibility with decreasing particle size may include proportional polyunsaturated fatty acid increases and decreased reducing systems (ubiquinol-10 and/or vitamin) per particle.

Small, Dense LDL In Normal And Pre-eclamptic Pregnancy:

The normal pregnancy rise in plasma triglyceride is associated with a shift from predominantly large and buoyant LDL (no pregnancy) to intermediate and small, dense LDL (36 week’s gestation), with partial reversal by 6 weeks postpartum. LDL size correlated negatively with triglycerides (R= -0.61, P<0.01).

Some studies measured the mass of three LDL sub fractions (LDL –I, II, and III) isolated on the basis of increasing density from plasma of women with preeclampsia and normal pregnancy. Preheparin hepatic lipase activity was increased in preeclampsia plasma that, by hydrolysis of LDL triglycerides, could partially explain predominance of small, dense LDL in the syndrome.

It is evident that not all women with preeclampsia exhibit smaller, denser LDL relative to normal pregnancy. Apart from size differences one component of pathophysiology in preeclampsia might be abnormal maternal or placental response to (or handling of) the small, dense LDL may impart substantial increases in LDL oxidation susceptibility. The intrinsic susceptibility of isolated LDL to Cu2+ mediated oxidation is increased in preeclampsia. Whether this is a function of LDL size shift or some unrelated LDL difference is presently unclear.
 In preeclampsia, however, evidence for the interaction of plasma lipids, reactive oxygen species, and endothelial cell dysfunction is largely indirect, In contrast to arteriosclerosis, for example, there are currently no positive or negative reports on isolation of oxidized lipids from vascular tissues in preeclampsia.


 For example, µ-tocopherol (µ-TOH) slows lipid peroxidation by scavenging lipid peroxyl radicals (LOO·). Ascorbate is thus a supreme reducing system nutrient. 133

 Reducing System Hazards and Clinical Trials:

There has been increasing interest in clinical trials of reducing systems for prevention or treatment or preeclampsia. The heterorganic function of reducing systems is exemplified by two different reducing system bioassays used to study preeclampsia. A substantial deficit in this serum reducing system activity is observed in preeclampsia relative to normal pregnancy because serum-transferring iron binding reserve (apotransferrin) is decreased. In contrast, reducing system activity measured as the ability of plasma to scavenge water-soluble peroxyl radicals is increased in preeclampsia and this is largely a function of increased uric acid concentrations. Xanthine oxidase produces uric acid (an reducing system) but can also be a major source of local reactive oxygen species, such as hydroxyl radicals (OH), can generate uric acid radicals that are themselves capable of causing cell damage. It would not be surprising if the effects of a xanthine-oxidase inhibitor, such as allopurinol, were complex in preeclampsia.

In one trial vitamin E supplementation failed to have a salutary effect on the course of already established preeclampsia, but as noted, plasma vitamin E deficiency is not a characteristic of the disorder. In another report, a randomized control trial in which a combination of reducing systems were given orally for 1-2 weeks) to women with established early-onset preeclampsia (usually severe), no changes in maternal placental thiobarbituric acid- reactive substances (an index of lipid peroxidation) and no alterations in glutathione concentration were noted. There was, however, a tendency for the treated group to deliver later. Also, decreased concentration of uric acid and increased concentrations of vitamin E, but no differences in thiobarbituric acid-reactive substance, were noted in the sera of these treated subjects.

In essence, although the potential for administering reducing systems to prevent or treat preeclampsia is appealing, we suggest that their incorporation into clinical care be deferred until (1) appropriate reducing systems can be established and (2) clinical trials demonstrate safety and efficacy for both mother and baby.


It is reported that regular exercise increases beneficial reducing systems in pregnant women, which in turn reduces oxidative stress.



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