Fructose might be a clue to the origin of preeclampsia insights from nature and evolution.

Preeclampsia is a hypertensive disorder of pregnancy and is due to abnormal placentation. The pathogenesis remains unclear. Fructose is biologically distinct from glucose and has a critical role in fetal growth in early pregnancy. Many species, including humans, produce fructose in their placenta during the first trimester to assist fetal growth and survival during a time when hypoxia is significant. Fructose is preferred over glucose in hypoxic tissues, and in the developing fetus, fructose has a critical role in stimulating the production of nucleic acids, lipids and glycosaminoglycans. Fructose production normally decreases significantly following the establishment of maternal-fetal circulation following placentation. However, if there is impaired placentation, local hypoxia will continue to drive fructose production. Excessive fructose metabolism drives endothelial dysfunction, oxidative stress, elevated blood pressure, insulin resistance, fatty liver, and a rise in uric acid and vasopressin levels, all of which are features of the preeclamptic state. In addition to fructose production, dietary fructose, for example, from soft drinks, would be additive and has been reported to be a strong independent risk factor for preeclampsia. Uric acid-associated endothelial dysfunction disturbs the invasion of the spiral artery, leading to placental ischemia and further placental hypoxia. Here, we summarize the previous literature regarding the physiological and pathological roles of fructose in pregnancy and propose studies to further investigate the pathogenesis of preeclampsia. Fructose might be a Clue to the Origin of Preeclampsia Insights from Nature and Evolution Preeclampsia is a hypertensive disorder of pregnancy. The pathogenesis remains unclear. Fructose has a critical role in fetal growth in early pregnancy, and might be a key role to developing preeclampsia. Here, we summarize the previous literatures regarding the physiological andpathological roles of fructose in pregnancy to propose studies to further investigate the pathogenesis of preeclampsia.

Receptor tyrosine kinase Tie-1 overexpression in endothelial cells upregulates adhesion molecules.

Tie-1 is an endothelial specific cell surface protein whose biology remains poorly understood. Using an overexpression system in vitro, we examined whether Tie-1 activity in endothelial cells in vitro would elicit a proinflammatory response. We found that when overexpressed in endothelial cells in vitro, Tie-1 is tyrosine-phosphorylated. We also showed that Tie-1 upregulates VCAM-1, E-selectin, and ICAM-1, partly through a p38-dependent mechanism. Interestingly, upregulation of VCAM-1 and E-selectin by Tie-1 is significantly higher in human aortic endothelial cells than in human umbilical vein endothelial cells. Additionally, attachment of cells of monocytic lineage to endothelial cells is also enhanced by Tie-1 expression. Collectively, our data show that Tie-1 has a proinflammatory property and may play a role in the endothelial inflammatory diseases such as atherosclerosis.

Trophoblast mitochondrial function is impaired in preeclampsia and correlates negatively with the expression of soluble fms-like tyrosine kinase 1.

Preeclampsia is a common medical complication of pregnancy that is associated with significant morbidity and mortality to the mother and the baby. Extensive human epidemiological and experimental studies suggest that excess placental soluble fms-like tyrosine kinase 1, a potent anti-angiogenic factor leads to the maternal hypertension, proteinuria and other systemic complications of preeclampsia. To evaluate the mechanisms of the aberrant placental sFlt1 expression, we studied the role of mitochondrial dysfunction as one possible etiological factor. Here, using human placental samples, we demonstrate that both the activity and expression of a mitochondrial electron transport chain enzyme cytochrome C oxidase (COX) is diminished in the syncytiotrophoblast layer of the chorionic villi from preeclamptic subjects. In addition, there was an inverse correlation between mitochondrial COX enzyme activity and placental sFlt1 expression. Functional in situ enzyme chemistry with electron microscopy also confirmed impaired mitochondrial function in preeclampsia. Ultrastructural and morphometric analysis of mitochondria using electron microscopy demonstrated, that mitochondria are smaller in both the syncytiotrophoblast and cytotrophoblast layers of preeclamptic tissue. The etiology of the mitochondrial dysfunction in preeclampsia as a cause or effect of the placental anti-angiogenic state remains to be elucidated in future studies.

Macrophage migration inhibitory factor as a novel biomarker of portopulmonary hypertension.

Portopulmonary hypertension (POPH) is a poorly understood complication of liver disease associated with significant morbidity and mortality. We sought to identify novel biomarkers of POPH disease presence and severity. We performed a prospective, multicenter, case-control study involving patients with liver disease undergoing right heart catheterization. POPH cases were defined as a mean pulmonary arterial pressure (mPAP) ≥25 mmHg and pulmonary vascular resistance (PVR) >240 dynes˙s˙cm-5. Plasma samples were collected from the systemic and pulmonary circulation, and antibody microarray was used to identify biomarkers. Characterization and validation of a candidate cytokine, macrophage migration inhibitory factor (MIF), was performed using enzyme-linked immunosorbent assay. Continuous variables were compared using a Mann-Whitney U test and correlated with disease severity using Spearman correlation. MIF levels were elevated in both the systemic and pulmonary circulation in patients with POPH compared with controls (median MIF level [interquartile range] in systemic circulation: 46.68 ng/mL [32.31-76.04] vs. 31.19 ng/mL [26.92-42.17], P = 0.009; in pulmonary circulation: 49.59 ng/mL [35.90-108.80] vs. 37.78 [21.78-45.53], P = 0.002). In patients with POPH, MIF levels were positively correlated with PVR (r = 0.58, P = 0.006) and inversely correlated with cardiac output (r = -0.57, P = 0.007). MIF >60 ng/mL or tricuspid regurgitation gradient >50 mmHg had a 92% sensitivity and specificity for the diagnosis of POPH, with a positive predictive value of 86% and a negative predictive value of 96%. MIF is a promising novel biomarker of POPH disease presence and severity in patients with liver disease and portal hypertension.

Correlation of cystatin-C with glomerular filtration rate by inulin clearance in pregnancy.

OBJECTIVE: To test utility of cystatin-C as a marker of glomerular filtration rate during pregnancy, we performed serial correlations with inulin clearance during pregnancy and postpartum. METHODS: Twelve subjects received inulin infusions and serum cystatin-C at three time points. Pearson's correlation coefficient was calculated. RESULTS: Cystatin-C levels ranged 0.66-1.48 mg/L during pregnancy, and 0.72-1.26 mg/L postpartum. Inulin clearance ranged 130-188 mL/min during pregnancy, and 110-167 mL/min postpartum. Cystatin-C did not correlate with inulin clearance at any time point. CONCLUSION: Serum cystatin-C did not correlate with inulin clearance during pregnancy or postpartum.

Angiogenic factors in the pathogenesis of preeclampsia.

Preeclampsia affects 5-10% of pregnancies and is responsible for substantial maternal and neonatal morbidity and mortality. It is believed to be a two-stage disease with an initial placental trigger with no maternal symptoms followed by a maternal syndrome characterized by hypertension, proteinuria, and endothelial dysfunction. The first stage is thought to be due to shallow cytotrophoblast invasion of maternal spiral arterioles leading to placental insufficiency. The diseased placenta in turn releases soluble angiogenic factors that induce systemic endothelial dysfunction and clinical preeclampsia during the second stage. This review will discuss the role of circulating angiogenic factors of placental origin as potential mediators of the systemic endothelial dysfunction and the clinical syndrome of preeclampsia and provide an evolutionary explanation for this phenomenon.