Increased signaling of various hormones through their cognate G Protein-Coupled Receptors (GPCRs), including the angiotensin, endothelin, and vasopressin systems, are implicated in human preeclampsia (PreE) and animal models of the disorder. Cascade-specific termination of GPCR signaling following receptor activation is catalyzed by the Regulator of G protein Signaling (RGS) family members. Within the RGS B/R4 family, RGS5 and RGS2 are implicated in human PreE and gestational hypertensive disorders. Mutations within the RGS2 gene, a B/R4 RGS member, are associated with human hypertensive populations and increased risk of developing PreE and its sequelae. Given the role for the placenta in the pathogenesis of PreE, we hypothesized a role for RGS2 in the placenta during PreE. My studies showed RGS2 mRNA expression is reduced in placentas from pregnancies affected by PreE. Reduced fetal-placental Rgs2 induces gestational hypertension, proteinuria, and increased plasma ALT activity in wildtype dams. Placentas with reduced Rgs2 expression exhibit reduced vascularization, increased thickness of the labyrinth and spongiotrophoblast layers, and enrichment for pathways associated with human PreE. Analysis of human PreE placenta samples reveals an increase in the cAMP/CREB signaling pathway, yet we demonstrate loss of CREB occupancy at the RGS2 promoter. HTR8 cell cultures indicate HDAC activity may be required CREB transcription of specific gene sets. In silico analysis supports this concept and further implies it may be impaired in human PreE placentas. These findings demonstrate heterozygous loss of fetal-placental Rgs2 is sufficient to induce PreE phenotypes in wildtype dams during pregnancy. Additionally, they highlight the role of the placenta in maternal pathogenesis of PreE and support the concept that paternal genetics influence the risk of developing PreE.

Von Hippel Lindau (VHL) is a tumour suppressor protein classically known to target the α subunit of hypoxia inducible factor (HIF) for proteasomal degradation. Emerging evidence has underscored a novel role for VHL in both cell cycle regulation and extracellular matrix assembly. Herein, we provide evidence of VHL multitasking in normal and pathological placentation. Using ex vivo, first trimester human placental tissue and in vitro, JEG-3 choriocarcinoma cell line model we demonstrate that VHL plays a role in regulating the expression of cell cycle modulator CCND1 via a mechanism involving its inhibitor, p15 and HIF-2α. In addition, using a similar experimental strategy we provide evidence supporting a role for VHL in regulating the expression of fibronectin and its receptor integrin α5. Moreover, altered VHL expression observed in preeclampsia is associated with altered expression of cell cycle regulators and contributes to altered FN protein levels which are characteristic of this pathology.

Von Hippel Lindau (VHL) is a tumour suppressor protein classically known to target the α subunit of hypoxia inducible factor (HIF) for proteasomal degradation. Emerging evidence has underscored a novel role for VHL in both cell cycle regulation and extracellular matrix assembly. Herein, we provide evidence of VHL multitasking in normal and pathological placentation. Using ex vivo, first trimester human placental tissue and in vitro, JEG-3 choriocarcinoma cell line model we demonstrate that VHL plays a role in regulating the expression of cell cycle modulator CCND1 via a mechanism involving its inhibitor, p15 and HIF-2α. In addition, using a similar experimental strategy we provide evidence supporting a role for VHL in regulating the expression of fibronectin and its receptor integrin α5. Moreover, altered VHL expression observed in preeclampsia is associated with altered expression of cell cycle regulators and contributes to altered FN protein levels which are characteristic of this pathology.

Objetivo General: Determinar la correlación clínica y de exámenes de laboratorio del Síndrome Hellp con los resultados materno - neonatales. Material y Métodos: Se realizó un estudio observacional longitudinal, retrospectivo correlacional, en pacientes como diagnostico Síndrome de Hellp, encontrándose en un lapso de tres años, un total de 153 casos; se correlacionó los resultados maternos y resultados neonatales con los parámetros de laboratorio que hacen el diagnóstico de Sd de Hellp. Para el análisis se usaron las pruebas t de student, para las variables paramétricas; y para las variables no paramétricas, se utilizó la prueba de Kruskal – Wallis, considerándose la significación estadística con un valor de p <0.05. Resultados: La incidencia del S. de Hellp fue de 0.76%, siendo la clase III la mas frecuente (60%), el 48% no tuvo CPN, la mayor parte de las gestaciones culminaron por cesárea (62.7%), siendo la clase I la que tuvo mas cesáreas; se observó que el edema pulmonar se encontró en la clase I, los vómitos están relacionados significativamente con malos resultados materno y neonatales, La epigastralgia se relaciona mejor con la clase I en el 50%, la eclampsia no guarda relación de causalidad con los niveles plaquetarios, los parámetros de laboratorio no guardan relación con resultados neonatales, la diferencia de resultados neonatales con el tipo de Hellp no fue observada, los preterminos se presentaron en el 44.3%, la ictericia se asocio mas a clases I y II con 50 y 41%, la mortalidad neonatal se observo mas con la clase 1 con 16.7%; en los RN se observo la relación directa de nauseas con muerte neonatal 25%, también de nauseas con sepsis neonatal (66.6%), finalmente se aprecia un mayor uso de hemoderivados en la Clase I, >66%. Conclusiones: La Clase de Hellp de mayor severidad se correlaciona con malos resultados maternos, mayor tasa de cesáreas, uso de hemoderivados, complicaciones oculares, pulmonares, uso de UCI, mayor tiempo de hospitalización, así como de malos resultados neonatales, sepsis y muerte neonatal; siendo el parámetro clínico de mayor importancia las nauseas y los vómitos, que se relacionan con malos resultados maternos; en cuanto a los niveles de plaquetas, los valores bajos se asocian a muerte y sepsis neonatal.

No description available.

Se presenta la investigación que tiene por objetivo principal establecer la asociación entre la severidad de la preeclampsia y la frecuencia con que se presentan las complicaciones en los recién nacidos de pacientes con preeclampsia leve y severa en relación a los recién nacidos de pacientes sin preeclampsia atendidas en el Hospital Nacional Sergio E. Bernales, durante el periodo de 01 de Junio al 30 de Noviembre del año 2004. Se realizó un estudio de Cohortes, comparando 102 y 37 recién nacidos de pacientes con preeclampsia leve y severa respectivamente con 139 recién nacidos de pacientes sin preeclampsia. El análisis estadístico de los datos se realizó con el programa SPSS 10.0 y EPIDAT, las frecuencias de las complicaciones fueron sometidas a una tabla de doble entrada, comparándose los tres grupos de estudio. El análisis estadístico de las variables se realizó utilizando la prueba Chi cuadrado y también mediante el cálculo de Riesgo Relativo, considerándose significativo un p<0.05 y p< 0.01 e intervalos de confianza al 95% y 99%.Se halló una incidencia de preeclampsia de 10.91%. Las complicaciones fueron mas frecuentes en los recién nacidos de pacientes con preeclampsia severa -excepto la depresión neonatal que fue mas frecuente en la preeclampsia leve- ellas son bajo peso al nacer, pequeño para la edad gestacional, prematuridad y trastornos metabólicos. Las complicaciones fueron 7.71 y 66.73 veces mayor en el grupo de recién nacidos de pacientes con preeclampsia leve y severa respectivamente en comparación con los nacidos de pacientes sin preeclampsia y 5.46 veces mayor al comparar los recién nacidos de pacientes con preeclampsia leve y severa. Hubieron 5 casos de muerte perinatal por preeclampsia. El control prenatal resultó un factor de riesgo asociado significativamente con la presentación de las complicaciones en los recién nacidos. La frecuencia y gravedad de las complicaciones que presentaron los recién nacidos dependieron de la progresión y severidad de la preeclampsia, se sugiere por ello un control prenatal adecuado y de calidad para las gestantes así como el manejo oportuno de la enfermedad con estrategias de intervención bien establecidas para el caso.

Preeclampsia is the leading cause of foetal and maternal mortality and morbidity in developing countries. In South Africa, maize is a dietary staple for most black African populations and is susceptible to contamination by mycotoxins such as fumonisin B1 (FB1).Fumonisin B1 is a ubiquitous secondary metabolite of Fusarium fungi produced predominantly by Fusarium verticillioides. This mycotoxin shares structural similarities with the backbone of sphingoid bases (sphinganine and sphingosine) which are substrates for the biosynthesis of complex sphingolipids. The mechanism of FB1 toxicity therefore is centred on the disruption of this process. The aim of the present study was to elucidate the possible causal link between FB1 and preeclampsia. Following ethical approval, 20 normotensive and 20 preeclamptic patients were recruited into the study. Blood and placental tissue were collected and processed for further analysis. The presence of FB1 was verified using standard immunohistochemical and electrophoretic techniques. The levels of FB1 and sphingolipids were quantified using high performance liquid chromatography (HPLC). Western blotting was conducted to confirm the presence of FB1 in the serum. Placental tissue apoptosis was evaluated using Hoechst staining and other markers. Lipid peroxidation was measured in serum and placental tissue of both groups. Fumonisin B1 was immunolocalised within the endothelial cells and mesenchymal cells of placentas from both groups, while FB1 was present in cytotrophoblastic cells of preeclamptic patients only. In addition, FB1 concentrations were significantly higher in preeclamptic compared to normotensive serum samples. Sphinganine was significantly elevated in preeclamptic serum samples whilst there was no statistical difference in the sphingosine levels between the groups. Chromatin condensation was higher in the preeclamptic patients. Caspase 3 and Fas were present with greater intensity in preeclamptic samples. The levels of lipid peroxidation were significantly higher in both serum and placental tissue of preeclamptic patients. This study has demonstrated not only the presence of FB1 in the serum and placental tissues of pregnant women but also the potential effects of this mycotoxin in the humans. / Thesis (M.Med.Sc.)-University of KwaZulu-Natal, Durban, 2012.

Prospective epidemiological studies indicate that regular exercise during the year prior to conception reduces preeclampsia risk, whereas exercise during affects pregnancy reduces preeclampsia risk only at specific dosages, or in specific subpopulations. The risk of severe preeclampsia is increased among women who exercise for more than 270 minutes/week in early pregnancy. Physiology studies are needed to identify mechanisms through which regular exercise may influence preeclampsia risk. This dissertation examined the effects of pregnancy (30-36 weeks gestation), and regular exercise participation, on two important pathophysiological features of preeclampsia; circulating anti-angiogenic markers, represented by soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), and endothelial dysfunction. The results demonstrate that regularly exercising, pregnant non-smoking women have higher levels of serum placental growth factor (PlGF), lower levels of serum sFlt-1 and sFlt-1:PlGF, and are less likely to experience high serum sEng levels, than sedentary women. The effects of exercise on PlGF and sFlt-1:PlGF are more pronounced among women exercising less than 270 minutes/week in pregnancy. Anti-angiogenic changes that could contribute to preeclampsia were not observed immediately after short-duration, moderate-intensity exercise in the third trimester. Flow-mediated dilation (FMD) and the shear stimulus for FMD are not affected by pregnancy, however the time to peak FMD was increased in pregnancy. Regular exercise did not affect FMD or its shear stimulus in healthy pregnant or non-pregnant women. FMD and its shear stimulus were positively correlated in active, but not inactive, pregnant and non-pregnant women. Pregnancy and physical activity do not affect radial artery low flow-mediated constriction (L-FMC). L-FMC is artery dependent, occurring in the radial, but not the brachial, artery of healthy pregnant and non-pregnant women. The positive correlation between L-FMC and FMD suggests that L-FMC and FMD are not independent measurements. The results of this thesis suggest that physical activity and exercise may reduce preeclampsia risk by reducing concentrations of angiogenic markers. Although exercise participation did not affect conduit artery vascular function in healthy pregnant women, future studies should investigate the effects of exercise on vascular function in women with endothelial dysfunction, or risk factors for preeclampsia. / Thesis (Ph.D, Kinesiology & Health Studies) -- Queen's University, 2009-06-11 12:41:53.466

Pre-eclampsia, often described as toxaemia of pregnancy, historically represents one of the most widely investigated conditions relating to human reproduction. To date no firm cure has been found and a clear, well defined mechanism has not been ascribed to the pathogenesis of the disease. Researchers seem to focus on single pathways in isolation of others. The disease rather represents a multitude of possible underlying pathologies nvolving genetics, immune dysregulation, vascular maladaptation, and sociobiological factors thus complicating the approach to treatment. However, a central theme is the presence of reduced placental perfusion resulting in a hypoxic and/or ischaemic placenta and the subsequent secretion of various factors that initiate the maternal syndrome. It is within this context that we examine how an intervention such as increasing placental perfusion may represent a promising treatment strategy for this disease. We sought to manipulate the vasodilatory mechanisms of the uterine vasculature using sildenafil citrate and a flavonoid extracted from Eriosema kraussianum (Kr2), in Sprague-Dawley rats that exhibited preeclampsia-like manifestations. Both treatment regimens improved fetal outcomes and reduced blood pressure amplification and proteinuria. They also reduced the plasma concentrations of the two anti-angiogenic factors; sFlt1 and sEng. Only sildenafil citrate improved nitric oxide levels which was expected, suggesting that Kr2 causes vasodilation by some other mechanism. Nevertheless, both compounds improved both pup and placental weights, suggesting that they also improve utero-placental perfusion. These findings that selective uterine vascular dilation improves placental perfusion may be promising in averting possible death to mothers and their babies from pre-eclampsia especially in low resource environments. / Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2011.

Adequate maternal, intervillous and fetal blood flow are all necessary for fetal wellbeing. Compromise to any part of this exchange would be detrimental to pregnancy outcome. Preeclampsia is associated with reduced maternal spiral artery flow, resulting in reduced placental perfusion. This in turn creates an ischemic environment which may pre-dispose morphological changes in placental villi. This pilot study utilized morphometric image analysis to examine some features of the fetal component of the placenta in normotensive (NT) and pre-eclamptic (PE) groups. The features examined included: density of placental villi (expressed as percentage of field area occupied by placental tissue); stem vessel carrying capacity (expressed as percentage of stem villus area occupied by vessel lumina); the thickness of the stem arterial walls relative to artery size (expressed as percentage of artery area occupied by arterial wall) and the extent of fibrosis associated with villi (expressed as percentage of field area occupied by fibrosis). The results were as follows: density of placental villus arrangement NT:51.89±6.19, PE:64.78±6.93 (P<0.001); carrying capacity of stem villi NT:17.20±11.78, PE:8.67±8.51 (P<0.001); relative thickness of stem villi arterial walls NT:74.08±12.92, PE: 86.85±10.55 (P<0.001); and extent of fibrosis NT:0.727±0.310, PE:1.582±0.707 (P<0.001). These significant differences between normotensive and pre-eclamptic placentae suggest possible fetal maladaptations in response to the intervillous ischemia, compounding the existing maternal compromise to materno-fetal exchange. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2012.