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Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous pre-eclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.

Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous pre-eclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.

Background24,25-Dihydroxyvitamin D [24,25(OH)2D] is a metabolite of 25-hydroxyvitamin D (25D). Blacks frequently have low total 25D without manifestations of vitamin D deficiency, suggesting that total serum 25D may incorrectly reflect vitamin D status in different racial groups. The ratio of serum 24,25(OH)2D to 25D [vitamin D metabolite ratio (VMR)] represents a new candidate biomarker for vitamin D status.MethodsWe measured 24,25(OH)2D3 and 25D3 by mass spectrometry in a random community cohort of black (n = 212) and white (n = 164) Americans to evaluate VMR as a marker for vitamin D status. We measured parathyroid hormone concentrations by immunoassay to compare VMR and 25D3 against a physiological indicator of vitamin D deficiency.ResultsSerum 24,25(OH)2D3 strongly correlated with 25D3 in both black and white study participants (r = 0.90, P < 0.001 and r = 0.86, P < 0.001 respectively). Blacks had lower mean 25D3 than whites [17.0 (7.8) vs 27.5 (11.3) ng/mL; 42.4 (19.5) vs 68.6 (28.2) nmol/L, P < 0.001] and lower mean 24,25(OH)2D3 [2.1 (1.3) vs 3.6 (2.0) ng/mL; 5.1 (3.1) vs 8.7 (4.8) nmol/L, P < 0.001]. In contrast to total 25D3 concentrations, mean VMR values were similar in blacks and whites [11.9 (4.0) vs 12.5 (3.4), P = 0.16, respectively] and were negatively correlated with parathyroid hormone concentrations in both races (rs = -0.26, P < 0.001, and rs = -0.25, P < 0.001, respectively).ConclusionsOur results provide further evidence that measurement of total 25D for assessment of vitamin D status in patients of African descent deserves reevaluation and suggest that alternative measures such as VMR should be considered.

Rationale: Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1), an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo. Objective: We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies. Methods and Results: Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone. Conclusion: Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein.

A growing body of evidence supports an association between vitamin D and cardiovascular disease. However, the mechanisms underlying this association are unknown. From 2000 to 2002, we identified 946 participants with stable cardiovascular disease in San Francisco, California, and followed them prospectively for cardiovascular events (heart failure, myocardial infarction, stroke, or cardiovascular death). We then examined the extent to which the association was attenuated by adjustment for poor health behaviors, comorbid health conditions, and potential biological mediators. During a median follow-up period of 8.0 years (through August 24, 2012), 323 subjects (34.1%) experienced a cardiovascular event. Following adjustment for sociodemographic factors, season of blood measurement, health behaviors, and comorbid conditions, 25-hydroxyvitamin D levels under 20 ng/mL remained independently associated with cardiovascular events (hazard ratio = 1.30, 95% confidence interval: 1.01, 1.67). However, after further adjustment for potential biological mediators, the independent association was no longer present (hazard ratio = 1.11, 95% confidence interval: 0.85, 1.44). Parathyroid hormone, a potentially modifiable biological factor downstream from 25-hydroxyvitamin D, was responsible for the majority of this attenuation. These findings highlight the need for randomized controlled trials to determine whether vitamin D supplementation in persons with deficiency could be beneficial for the primary or secondary prevention of cardiovascular events.

Rationale: Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1), an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo. Objective: We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies. Methods and Results: Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone. Conclusion: Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein.

Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD), characterized by marked inflammation and severe fibrosis of the peritoneum, and associated with high morbidity and mortality. EPS can occur years after termination of PD and, in severe cases, leads to intestinal obstruction and ileus requiring surgical intervention. Despite ongoing research, the pathogenesis of EPS remains unclear. We performed a global transcriptome analysis of peritoneal tissue specimens from EPS patients, PD patients without EPS, and uremic patients without history of PD or EPS (Uremic). Unsupervised and supervised bioinformatics analysis revealed distinct transcriptional patterns that discriminated these three clinical groups. The analysis identified a signature of 219 genes expressed differentially in EPS as compared to PD and Uremic groups. Canonical pathway analysis of differentially expressed genes showed enrichment in several pathways, including antigen presentation, dendritic cell maturation, B cell development, chemokine signaling and humoral and cellular immunity (P value<0.05). Further interactive network analysis depicted effects of EPS-associated genes on networks linked to inflammation, immunological response, and cell proliferation. Gene expression changes were confirmed by qRT-PCR for a subset of the differentially expressed genes. EPS patient tissues exhibited elevated expression of genes encoding sulfatase1, thrombospondin 1, fibronectin 1 and alpha smooth muscle actin, among many others, while in EPS and PD tissues mRNAs encoding leptin and retinol-binding protein 4 were markedly down-regulated, compared to Uremic group patients. Immunolocalization of Collagen 1 alpha 1 revealed that Col1a1 protein was predominantly expressed in the submesothelial compact zone of EPS patient peritoneal samples, whereas PD patient peritoneal samples exhibited homogenous Col1a1 staining throughout the tissue samples. The results are compatible with

Oxidative stress is widely implicated in failed reproductive performance including infertility, miscarriage, diabetes-related congenital malformations and preeclampsia. Maternal obesity is a strong risk factor for preeclampsia, and recently, in an animal model of maternal obesity we have reported evidence of oxidative stress in the oocytes of obese animals prior to pregnancy as well as in early stage embryos. This adds to the growing evidence for a greater focus on the pre-conceptual period in prevention of pregnancy disorders including those related to oxidative stress. Our research has also focussed on the role of free radicals and antioxidant capacity in preeclampsia. Assessment by measurement of markers of lipid peroxidation or of antioxidant capacity has provided unequivocal evidence for oxidative stress in this disorder. Partial failure of the process of placentation has been implicated, with recent evidence proposing that ischaemia-reperfusion in the placenta may contribute to oxidative stress in trophoblast. Endoplasmic reticulum stress in the placenta may also play a role. We and others have performed randomised controlled trials to determine whether early supplementation with vitamins C and E in women at risk of preeclampsia may be beneficial but these studies have shown no evidence for prevention of preeclampsia. Whether this represents an inappropriate antioxidant strategy or whether supplementation has been too late in gestation to be beneficial is not known. Other potential approaches to prevention of preeclampsia through amelioration of oxidative stress include provision of supplements in the pre-conceptual period, selenium supplements, anti-peroxynitrite strategies and statins.

Oxidative stress is widely implicated in failed reproductive performance including infertility, miscarriage, diabetes-related congenital malformations and preeclampsia. Maternal obesity is a strong risk factor for preeclampsia, and recently, in an animal model of maternal obesity we have reported evidence of oxidative stress in the oocytes of obese animals prior to pregnancy as well as in early stage embryos. This adds to the growing evidence for a greater focus on the pre-conceptual period in prevention of pregnancy disorders including those related to oxidative stress. Our research has also focussed on the role of free radicals and antioxidant capacity in preeclampsia. Assessment by measurement of markers of lipid peroxidation or of antioxidant capacity has provided unequivocal evidence for oxidative stress in this disorder. Partial failure of the process of placentation has been implicated, with recent evidence proposing that ischaemia-reperfusion in the placenta may contribute to oxidative stress in trophoblast. Endoplasmic reticulum stress in the placenta may also play a role. We and others have performed randomised controlled trials to determine whether early supplementation with vitamins C and E in women at risk of preeclampsia may be beneficial but these studies have shown no evidence for prevention of preeclampsia. Whether this represents an inappropriate antioxidant strategy or whether supplementation has been too late in gestation to be beneficial is not known. Other potential approaches to prevention of preeclampsia through amelioration of oxidative stress include provision of supplements in the pre-conceptual period, selenium supplements, anti-peroxynitrite strategies and statins.

Oxidative stress is widely implicated in failed reproductive performance including infertility, miscarriage, diabetes-related congenital malformations and preeclampsia. Maternal obesity is a strong risk factor for preeclampsia, and recently, in an animal model of maternal obesity we have reported evidence of oxidative stress in the oocytes of obese animals prior to pregnancy as well as in early stage embryos. This adds to the growing evidence for a greater focus on the pre-conceptual period in prevention of pregnancy disorders including those related to oxidative stress. Our research has also focussed on the role of free radicals and antioxidant capacity in preeclampsia. Assessment by measurement of markers of lipid peroxidation or of antioxidant capacity has provided unequivocal evidence for oxidative stress in this disorder. Partial failure of the process of placentation has been implicated, with recent evidence proposing that ischaemia-reperfusion in the placenta may contribute to oxidative stress in trophoblast. Endoplasmic reticulum stress in the placenta may also play a role. We and others have performed randomised controlled trials to determine whether early supplementation with vitamins C and E in women at risk of preeclampsia may be beneficial but these studies have shown no evidence for prevention of preeclampsia. Whether this represents an inappropriate antioxidant strategy or whether supplementation has been too late in gestation to be beneficial is not known. Other potential approaches to prevention of preeclampsia through amelioration of oxidative stress include provision of supplements in the pre-conceptual period, selenium supplements, anti-peroxynitrite strategies and statins.

Oxidative stress is widely implicated in failed reproductive performance including infertility, miscarriage, diabetes-related congenital malformations and preeclampsia. Maternal obesity is a strong risk factor for preeclampsia, and recently, in an animal model of maternal obesity we have reported evidence of oxidative stress in the oocytes of obese animals prior to pregnancy as well as in early stage embryos. This adds to the growing evidence for a greater focus on the pre-conceptual period in prevention of pregnancy disorders including those related to oxidative stress. Our research has also focussed on the role of free radicals and antioxidant capacity in preeclampsia. Assessment by measurement of markers of lipid peroxidation or of antioxidant capacity has provided unequivocal evidence for oxidative stress in this disorder. Partial failure of the process of placentation has been implicated, with recent evidence proposing that ischaemia-reperfusion in the placenta may contribute to oxidative stress in trophoblast. Endoplasmic reticulum stress in the placenta may also play a role. We and others have performed randomised controlled trials to determine whether early supplementation with vitamins C and E in women at risk of preeclampsia may be beneficial but these studies have shown no evidence for prevention of preeclampsia. Whether this represents an inappropriate antioxidant strategy or whether supplementation has been too late in gestation to be beneficial is not known. Other potential approaches to prevention of preeclampsia through amelioration of oxidative stress include provision of supplements in the pre-conceptual period, selenium supplements, anti-peroxynitrite strategies and statins.