WRITE UPS - OBSTETRIC VASCULOPATHY - Pre-Eclampsia :A Different Face



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 present the most popular theory is that of oxidative stress, that leads 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.1 This chapter reviews these oxidative stress and the current status of reducing systems like Vit. C and E in pre-eclampsia.

One hypothesis receiving a great deal of attention is that placental and maternal factors converge to generate “oxidative stress” (an imbalance between oxidant and reducing system or reducing forces in favor of oxidants), promoting a vicious cycle of events that compromise the “defensive” vasodilatory, antiaggregatory, and barrier functioning of the vascular endothelium. Problems relating to maternal constitution, such as abnormal lipid metabolism and associated insulin resistance may be particularly important in this regard.



Free Radicals And Reactive Oxygen Species:

There are comprehensive reviews on interactions between reactive oxygen species and reducing systems in human health and disease. A wide spectrum of reactive oxygen species function as signal transducers in normal physiology but their overproduction may result in, or is the result of, a number of human health problems. Overproduction of reactive oxygen species can arise from a variety of sources, both environmental and metabolic. 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. These studies were carried out to test a hypothesis that suggests that pre-eclampsia is associated with inadequate control by the thioredoxin system and other related reducing systems. 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.

 Lipid Peroxidation:

Lipid peroxidation has received a great deal of attention in preeclampsia. The process can be described as oxidative deterioration of polyunsaturated fatty acids. 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:

Research focusing on arteriosclerosis has aptly demonstrated that the vascular endothelium is prone to damage from reactive oxygen species. Because vascular endothelial cells interface with blood, they are exposed to a variety of prooxidants including heme compounds and reactive species from activated neutrophils and platelets. Circulating lipids have diverse effects upon endothelial cell function, and dyslipidemia is associated with endothelial cell dysfunction. In particular, there is a considerable interest in the role played by low-density lipoprotein (LDL) oxidation in endothelial disturbances. LDL particles can undergo oxidation in vivo and such modification contributes to arterial lesions in arteriosclerosis and diabetes. The LDL particles continuously enter and exit the artery wall. In the sub endothelial interstitial matrix, LDL, may be exposed more frequently to cell derived oxidants and at the same time are less protected by reducing systems relative to circulating LDL. This potential for prolonged contact between LDL and the cell makes the sub endothelial space the likely site of LDL oxidation and is one reason the endothelium is a likely target for oxidized LDL-mediated disturbances 51-53. As will be discussed later in this chapter, the appearance of hypertriglyceridemia followed by increased prevalence of smaller, more oxidation-susceptible LDL particles might contribute to endothelial dysfunction in preeclampsia. Continued oxidation is facilitated (primed) by “feed-forward” interaction of lipid hydroperoxides in the LDL particle with cell-derived oxidants. These more extensive changes lead to recognition by the macrophage scavengers and synthesis of oxidized LDL antibodies.


The deleterious effects of lipid peroxidation (including peroxidation of LDL) on the vasclature include inhibition of endothelium-dependent relaxation. 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.


The hypothesis that the etiology of preeclampsia is related to deficient trophoblast invasion and failure of uterine artery remodeling is well founded. Defective arterial remodeling in preeclampsia and in intrauterine growth restriction (IUGR) results in reduced uteroplacental perfusion, which may predispose to episodes of placental hypoxia or ischemia. Placental infarcts occur with increased frequency in preeclampsia, consistent with focal hypoxia/ischemia.

 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. Nitric Oxide (NO) is a potent vasodilator released by endothelial cells. It is synthesized by the catalytic action of the endothelial constitutive nitric oxide synthase (ecNOS). Moreover, the synthesis of NO in normal human placental vasculature has already been established and impairment of the uteroplacental blood flow in pregnancies complicated by PE and/or IUGR has been demonstrated.

 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. Oxidative stress such as occurs in pre-eclampsia can alter expression of SOD isoforms. 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)



 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 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.



Non-enzymatic, low molecular mass reducing systems are the primary protestants against oxidative damage in the extra cellular compartment. They protect by reacting with radicals faster than radicals can react with potential targets and because anti oxidant radicals formed during electron transfer are usually less reactive than the initial inciting radical. Whether a molecule acts as an oxidant or reductant in any given interaction can often be predicted from tables of standard one-electron reduction potentials. For example, µ-tocopherol (µ-TOH) slows lipid peroxidation by scavenging lipid peroxyl radicals. Ascorbate is thus a supreme reducing system nutrient.

 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-transferrin 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.



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