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Here, the ligand binding, activation, and tissue distribution of the orphan G protein-coupled receptor (GPCR) GPR92 were studied. GPR92 binds and is activated by compounds based on the lysophosphatidic acid (LPA) backbone. The binding of LPA to GPR92 was of high affinity (K D ϭ 6.4 Ϯ 0.9 nM) and led to an increase in both phosphoinositide hydrolysis and cAMP production. GPR92 is atypical in that it has a low sequence homology with the classic LPA 1-3 receptors (21-22%). Expression of GPR92 is mainly found in heart, placenta, spleen, brain, lung, and gut. Notably, GPR92 is highly expressed in the lymphocyte compartment of the gastrointestinal tract. It is the most abundant GPCR activated by LPA found in the small intestinal intraepithelial CD8 ϩ cytotoxic T cells.

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P reeclampsia remains a major problem worldwide for mothers and babies. It is estimated that yearly 50 000 women die in developing countries from preeclampsia.1 Careful maternal observation for the signs of preeclampsia and delivery of women with increasingly severe preeclampsia is the cornerstone of management (as it has been for the past 100 years). Maternal mortality is, therefore, much less in developed countries with the capacity for careful perinatal observation, but morbidity is considerable and remains the leading cause of admissions to intensive care for pregnant women.2 Also, the appropriate delivery of women who develop increasingly severe preeclampsia early in gestation accounts for 8% of all preterm births. Why No Advances in Clinical Management?During the past 20 years, there has been an explosion in our knowledge of preeclampsia. The recognition of inflammation, including endothelial dysfunction as potential unifying pathophysiological concepts and the appreciation of the multisystemic nature of preeclampsia, has directed attention away from blood pressure as the sole or even most important pathophysiological issue of preeclampsia. 4 This concept has resulted in recognition of other origins of organ dysfunction. Despite this, we have not managed to affect the management or early recognition of preeclampsia with this information. Large, well-designed multicenter, clinical intervention trials have, at best, demonstrated a minimal effect on outcome except in perhaps the highest risk cases. Attempts to use factors implicated in the pathophysiology of the disorder to predict preeclampsia have also not as yet provided adequate sensitivity and specificity to be adopted for use in routine clinical practice. 5Is There >1 Subtype of Preeclampsia?Why is this? A recurring theme is success in small studies of prediction, prevention, or treatment of preeclampsia, and failure in larger adequately powered multicenter trials. This Abstract-Preeclampsia remains a major problem worldwide for mothers and babies. Despite intensive study, we have not been able to improve the management or early recognition of preeclampsia. At least part of this is because of failure to standardize the approach to studying this complex syndrome. It is possible that within the syndrome there may be different phenotypes with pathogenic pathways that differ between the subtypes. The capacity to recognize and to exploit different subtypes is of obvious importance for prediction, prevention, and treatment. We present a strategy for research to study preeclampsia, which will allow discrimination of such possible subtypes and also allow comparison and perhaps combinations of findings in different studies by standardized data and biosample collection. To make studies relevant to current clinical practice, the definition of preeclampsia can be that currently used and accepted. However, more importantly, sufficient data should be collected to allow other diagnostic criteria to be used and applied retrospectively.To that end, we present what we ...

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Preeclampsia is a leading cause of pregnancy complications and affects 3–7% of pregnant women. This review summarizes the current knowledge of a new potential etiology of the disease, with a special focus on hemoglobin-induced oxidative stress. Furthermore, we also suggest hemoglobin as a potential target for therapy. Gene and protein profiling studies have shown increased expression and accumulation of free fetal hemoglobin in the preeclamptic placenta. Predominantly due to oxidative damage to the placental barrier, fetal hemoglobin leaks over to the maternal circulation. Free hemoglobin and its metabolites are toxic in several ways; (a) ferrous hemoglobin (Fe2+) binds strongly to the vasodilator nitric oxide (NO) and reduces the availability of free NO, which results in vasoconstriction, (b) hemoglobin (Fe2+) with bound oxygen spontaneously generates free oxygen radicals, and (c) the heme groups create an inflammatory response by inducing activation of neutrophils and cytokine production. The endogenous protein α1-microglobulin, with radical and heme binding properties, has shown both ex vivo and in vivo to have the ability to counteract free hemoglobin-induced placental and kidney damage. Oxidative stress in general, and more specifically fetal hemoglobin-induced oxidative stress, could play a key role in the pathology of preeclampsia seen both in the placenta and ultimately in the maternal endothelium.

Preeclampsia is a major cause of morbidity and mortality during pregnancy. To date, the pathogenesis of the disease is not fully understood. Recent studies show that preeclampsia is associated with overexpression of hemoglobin genes α2 and γ and accumulation of the protein in the vascular lumen of the placenta. Hypothesizing that cell-free hemoglobin leaks from the placenta into the maternal circulation and contributes to the endothelial damage and symptoms by inducing oxidative stress, we analysed fetal and adult hemoglobin (HbF, HbA), haptoglobin, oxidation markers and the heme scavenger and antioxidant α 1 -microglobulin in plasma, urine and placenta in preeclamptic women (n=28) and normal pregnancies (n=27).The mean plasma concentrations of HbF, HbA, protein carbonyl groups, membrane peroxidation capacity and α 1 -microglobulin were significantly increased in preeclamptic women. The levels of total plasma Hb correlated strongly with the systolic blood pressure.The plasma haptoglobin concentrations of women with preeclampsia were significantly depressed. Increased amounts of α 1 -microglobulin-mRNA and protein were found in placenta from preeclamptic women and the levels of plasma and placenta α 1 -microglobulin correlated to plasma Hb-concentrations. The heme-degrading form t-α 1 -microglobulin was significantly increased in urine in preeclampsia. These results support that hemoglobin-induced oxidative stress is a pathogenic factor in preeclampsia.