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Query: UNIPROT:P06889 (Mol)
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The gonadotropins, whose members are human chorionic gonadotropin (hCG), lutenizing hormone (LH) and follicle-stimulating hormone (FSH) are a well characterized hormone family known to regulate reproductive functions in both females and males. Recent studies indicate that they can modulate the vascular system of reproductive organs. It was shown that gonadotropins not only influence the expression of vascular endothelial growth factor (VEGF) and both its receptors VEGFR-1 and -2, but also modulate other ubiquitously expressed angiogenic factors like the angiopoietins and their receptor Tie-2, basic fibroblast growth factor or placental-derived growth factor. Some recent data indicates a possible direct action of gonadotropins on endothelial cells. Thus, the gonadotropins act as tissue-specific angiogenic factors providing an optimal vascular supply during the menstrual cycle and early pregnancy in the female reproductive tract as well as in testis. In pathological conditions (e.g. preeclampsia, intrauterine growth restriction, ovarian hyperstimulation or endometriosis), these tightly regulated interactions between the gonadotropins and the ubiquitous angiogenic factors appear to be disturbed. The intent of this short manuscript is to review the current knowledge of the regulatory role of the gonadotropins in vasculo- and angiogenesis. We also review angiogenic actions of thyroid-stimulating hormone (TSH), a glycoprotein closely related to gonadotropins, which display strong gonodal actions.
Mol Cell Endocrinol 2007 Apr 15
PMID:The gonadotropins: tissue-specific angiogenic factors? 1734 37

Various hypotheses as to the origin of preeclampsia have been explored over time. Diseases of pregnancy are difficult to study for several reasons. One limitation is due to the fact that preeclampsia and associated diseases clinically present in the second and third trimenon, but seem to originate early in pregnancy. Comparisons with animal models are difficult due to the unique human nature of the disease. The creation of new methods including proteomics, genomics, lipidomics, metabolomics or mRNA microarray techniques supplement the traditional type of research access to approach mother and fetus. The clinical course will be discussed and pregnancy-related processes, which are thought to contribute to the disease. This includes implantation of the placenta/fetus, the adaptation of the endothelial activity to the pregnancy with respect to relaxin, matrix metalloproteinases and endothelin, nitric oxide, angiogenetic factors and TGF-b in normal and preeclamptic pregnancies. Furthermore, oxidative stress, genetics and hypothesis-generating molecular approaches are considered.
Mol Aspects Med 2007 Apr
PMID:Molecular aspects of preeclampsia. 1741 11

Recent data demonstrate that an altered immune response may play a key role in the development of preeclampsia. Some epidemiological findings and animal models support this idea. In this article, we review the innate immune system and adaptive immune system in preeclampsia and discuss the pathophysiology of preeclampsia from an immunological viewpoint. The most characteristic immunological finding in preeclampsia is the activation of both the innate and adaptive immune system. Activated neutrophils, monocytes, and NK cells initiate inflammation which induce endothelial dysfunction, and activated T cells may support inadequate tolerance during pregnancy. The cytokine profile in preeclampsia shows that the production of type 1 cytokines, which induce inflammation, is dominant while the production of type 2 cytokines, which regulates inflammation, is suppressed. Furthermore, the immunoregulatory system is down-regulated in preeclampsia and persistent inflammation reduces regulatory T cell function. Therefore, systematical immunoactivation may be one cause of preeclampsia.
Mol Aspects Med 2007 Apr
PMID:The role of the immune system in preeclampsia. 1743 31

Preeclampsia is a hypertensive disorder unique to pregnancy and remains the leading cause of maternal and fetal morbidity and mortality. Despite active research, the etiology of this disease remains still an enigma. There is increasing evidence that a combination of several factors is responsible for the development of preeclampsia. In this review, we discuss the role of aldosterone in the regulation of body fluid in pregnancy and preeclampsia. Aldosterone is produced by the enzyme aldosterone synthase and competes with cortisol and progesterone for the mineralocorticoid receptor, thus affecting sodium reabsorption and maternal volume expansion. Aldosterone seems to play a pivotal role in controlling blood pressure during pregnancy and to contribute to the well-being of the mother-to-be. Novel findings in understanding the underlying causes of preeclampsia provide a rationale for future novel prophylactic and therapeutic interventions in the treatment of this pregnancy-associated disease.
Mol Aspects Med 2007 Apr
PMID:Role of aldosterone availability in preeclampsia. 1751 81

Pre-eclampsia, a pregnancy-specific disorder, contributes substantially to perinatal morbidity and mortality of both, mother and newborn. An increasing number of biochemical agents were evaluated as markers for predicting pre-eclampsia. None of them has been proved to be of clinical value yet. Much effort has been put into assessing novel potential markers and their combination with other screening methods such as Doppler sonography. The purpose of this review is to reflect the current knowledge of serum markers for predicting pre-eclampsia. So far, the most promising serum markers are placental protein 13 (PP-13), as well as soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PIGF) and soluble endoglin (sEng). These markers allow screening at a relatively early stage and, most importantly, show relatively high predictive values and improved diagnostic performance if combined with first trimester Doppler sonography. Large-scale prospective studies, assessing these markers, are important to justify their clinical use in view of early intervention to prevent pre-eclampsia in the future.
Mol Aspects Med 2007 Apr
PMID:Serum markers for predicting pre-eclampsia. 1753 61

Cortisol availability is controlled by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which inactivates cortisol in cortisone, unable to bind to the glucocorticoid receptor. The 11beta-HSD2 enzyme activity limits either intracellular cortisol concentrations or within the uteroplacental compartment the transfer of cortisol into the fetal circulation. Mechanisms, by which 11beta-HSD2 activity is controlled, include transcriptional control, posttranscriptional modifications of 11beta-HSD2 transcript half-life, epigenetic regulation via methylation of genomic DNA and direct inhibition of enzymatic activity. The 11beta-HSD2 expression and activity is reduced in preeclampsia and the enzyme activity correlates with factors associated with increased vasoconstriction, such as an increased angiotensin II receptor subtype 1 expression, and notably fetal growth. Numerous signals such as proinflammatory cytokines known to be present and/or elevated in preeclampsia regulate 11beta-HSD2 activity. Shallow trophoblast invasion with the resulting hypoxemia seems to critically reduce available 11beta-HSD2 activity. A positive feedback exists as activated glucocorticoid receptors do enhance 11beta-HSD2 mRNA transcription and mRNA stability. No data are currently available on pregnancy and either epigenetic or direct effects on the activity of the translated enzyme.
Mol Aspects Med 2007 Apr
PMID:11beta-Hydroxysteroid dehydrogenase type 2 in pregnancy and preeclampsia. 1753 62

The origin of preeclampsia, a disease unique to pregnancy is still matter of debate and numerous theories have been proposed. The pathophysiology of the disease involves impaired trophoblast invasion, abnormal genetic polymorphism, vascular endothelial cell activation, immune intolerance by the maternal immune system, but also an exaggeration of a systemic inflammatory process. Preeclampsia is one of the major causes of maternal and perinatal morbidities including preterm births and therefore merits ongoing intensive research. The inflammatory process is determined by immunogenetic and non-immunogenetic factors. While inflammation mostly appears to be related to immunogenic determinants such as HLA antigens, paternity, monocytes, proinflammatory cytokines and NK cells, also responses not directly related to the immune system have been observed such as related to hypoxia or agonistic autoantibodies directed against vasoconstrictive angiotensin II receptors. The HIF-modulated reactions open up a new field in research as recently published data show the complexity of these factors.
Mol Aspects Med 2007 Apr
PMID:Inflammatory response in preeclampsia. 1753 63

Although preeclampsia (PE) is a major cause of maternal and fetal mortality, its pathogenesis is not fully understood. Digitalis-like cardiotonic steroids (CTS) are believed to be involved in the pathophysiology of PE, as illustrated by clinical observations that DIGIBIND, a digoxin antibody which binds CTS, lowers blood pressure in PE. Recently we reported that plasma levels of marinobufagenin (MBG), a vasoconstrictor CTS, are increased fourfold in patients with severe PE. In the present study, we tested whether anti-MBG, or anti-ouabain antibodies, or DIGIBIND can reverse inhibition of erythrocyte Na/K-ATPase (NKA) from patients with mild PE (blood pressure, 149 +/- 3/93 +/- 3 mm Hg; age, 28 +/- 2 years; gestational age, 37 +/- 1 weeks). Development of PE was associated with twofold rise in plasma MBG levels (1.58 +/- 0.15 vs. 0.80 +/- 0.11 nmol/L; P<0.01). The activity of erythrocyte NKA in 12 patients with PE was lower than in 6 normotensive gestational age-matched subjects (1.56 +/- 0.18 vs. 3.11 +/- 0.16 micromol Pi/ml/hr; P<0.001). In vitro treatment of erythrocytes from PE patients with anti-MBG antibody fully restored the NKA activity (3.26 +/- 0.41 micromol Pi/ml/hr; P<0.01). The effects of DIGIBIND was marginally significant (2.53 +/- 0.32 micromol Pi/ml/hr), while the anti-ouabain antibody was not effective (2.25 +/- 0.25 micromol Pi/ml/hr, P>0.5). The present observations provide evidence for a role for MBG in the pathogenesis of PE, and suggest that antibodies against MBG may be useful in the treatment of this syndrome.
Cell Mol Biol (Noisy-le-grand) 2006 Dec 30
PMID:Endogenous Na/K-ATPase inhibitors in patients with preeclampsia. 1753 31

Preeclampsia (PE), Hemolysis Elevated Liver Enzymes and Low Platelets (HELLP)-syndrome, and intrauterine growth restriction (IUGR) are associated with abnormal placentation. In early pregnancy, placental cytotrophoblasts fuse and form multinuclear syncytiotrophoblasts. The envelope gene of the human endogenous retrovirus-W, Syncytin, is a key factor for mediating cell-cell fusion of cytotrophoblasts. This study investigated clinical parameters of PE and HELLP-associated IUGR and analyzed the cell-cell fusion index and beta-human chorionic gonadotropin (beta-hCG) secretion of cytotrophoblasts isolated and cultured from placentas of these patients. In addition, we performed absolute quantitation of Syncytin and determined the apoptosis rate in both cultured cytotrophoblasts and placental tissues. Cultured cytotrophoblasts from PE and HELLP-associated IUGR correlated with a pronounced lower cell-cell fusion index, 1.8- and 3.6-fold; less nuclei per syncytiotrophoblast, 1.4- and 2.0-fold; a significantly decreased beta-hCG secretion, 4.3- and 17.2-fold and a reduction of Syncytin gene expression, 8.1 (P = 0.019) and 222.7-fold (P = 0.011) compared with controls, respectively. In contrast, a significantly 2.3-fold higher apoptosis rate was observed in cultured PE/IUGR cytotrophoblasts (P = 0.043). Importantly, Syncytin gene expression in primary placental tissues of PE/IUGR was 5.4-fold lower (P = 0.047) and in HELLP/IUGR 10.6-fold lower (P = 0.019) along with a 1.8- and 1.9-fold significant increase in the apoptosis rate compared with controls, respectively. Low Syncytin expression in both cultured cytotrophoblasts and primary tissues from pathological placentas supports an intrinsic placenta-specific deregulation of cell-cell fusion in the formation of syncytiotrophoblasts leading to increased apoptosis. These processes could contribute to the development and severity of PE and HELLP-associated IUGR.
Mol Reprod Dev 2008 Jan
PMID:Impaired cytotrophoblast cell-cell fusion is associated with reduced Syncytin and increased apoptosis in patients with placental dysfunction. 1754 32

Pregnancy-induced hypertension (PIH), also known as preeclampsia, is one of the major causes of maternal and fetal death. While the precise cause of PIH is not known, aberrant cytokine production and placenta participation are considered to be important factors. Gestational cigarette smoking, which is widely accepted to be harmful to both the mother and fetus, is protective against PIH. Based on the antiinflammatory activity of nicotine, the major component of cigarettes, we examined the effect of nicotine and other cholinergic agonists on placental inflammatory responses ex vivo. We observed that nicotine and other cholinergic agonists significantly suppress placenta cytokine production following stimulation. Placenta cells express the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), and using cholinergic antagonists, we demonstrated that the antiinflammatory effect of nicotine and other cholinergic agonists is, in part, mediated through the nAChR pathway. By contrast, cholinergic stimulation had no effect on the expression of soluble fms-like tyrosine kinase (sFlt), an antiangiogenic substance implicated in maternal vascular dysfunction during PIH. Mechanistic studies reveal that cholinergic agonists exert their antiinflammatory effects through the NFkappaB pathway. Taken together, our results suggest that cholinergic agonists, including nicotine, may reduce cytokine production by placenta cells via NFkappaB to protect against PIH.
Mol Med
PMID:Nicotine inhibits cytokine production by placenta cells via NFkappaB: potential role in pregnancy-induced hypertension. 1787 27


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