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Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.
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PMID:Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. 1261 13

Preeclampsia, the de novo occurrence of hypertension and proteinuria after the 20th week of gestation, continues to exert an inordinate toll on mothers and children alike. Recent clinical trials, new physiologic insights, and novel observations on pathogenesis have altered the thinking about preeclampsia. The mechanisms surrounding relaxin and its effects on the circulation and on matrix metalloproteinases have been elucidated. The growth factor's receptor, fms-like tyrosine kinase 1, has been shown to exist in a soluble form that is able to inactivate vascular endothelial-derived growth factor and human placental growth factor. Compelling evidence has been brought forth suggesting that fms-like tyrosine kinase 1 is a circulating factor that can cause preeclampsia. Preeclamptic women have high circulating levels of asymmetric dimethyl arginine that could account for the generalized endothelial dysfunction observed in preeclampsia. Preeclamptic women also produce novel autoantibodies that may serve to activate angiotensin receptors. These new observations raise the possibility that the treatment of preeclamptic women will soon be improved.
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PMID:New aspects in the pathophysiology of preeclampsia. 1533 93

Despite intensive research, preeclampsia still accounts for significant morbidity and mortality for the mother and the neonate, especially in developing countries. Recent studies have suggested that excess secretion of a naturally occurring anti-angiogenic molecule of placental origin referred to as soluble fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1) may contribute to the pathogenesis of preeclampsia. sFlt-1 acts by antagonizing two pro-angiogenic molecules - vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). Abnormalities in the angiogenic balance have been proposed as having a major role in the molecular cascade leading to proteinuria, hypertension, and endothelial dysfunction. Further evidence supports the hypothesis that angiogenic balance is crucial to differentiation and invasion of cytotrophoblasts. The abnormal placentation and the accompanying hypoxia may, in turn, result in more sFlt-1 production, thus leading to a vicious cycle of sFlt-1 production, eventually causing preeclampsia. These recent discoveries may facilitate the development of novel strategies for the diagnosis and therapy of preeclampsia.
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PMID:Recent advances in understanding of preeclampsia. 1615 64

Preeclampsia is a major cause of maternal, fetal, and neonatal mortality worldwide. Although the etiology of preeclampsia is still unclear, recent studies suggest that its major phenotypes, high blood pressure and proteinuria, are due in part to excess circulating soluble fms-like tyrosine kinase-1 concentrations. Soluble fms-like tyrosine kinase-1 is an endogenous antiangiogenic protein that is made by the placenta and acts by neutralizing the proangiogenic proteins vascular endothelial growth factor and placental growth factor. High serum soluble fms-like tyrosine kinase-1 and low serum free placental growth factor and free vascular endothelial growth factor have been observed in preeclampsia. Abnormalities in these circulating angiogenic proteins are not only present during clinical preeclampsia but also antedate clinical symptoms by several weeks. Therefore, this raises the possibility of measuring circulating angiogenic proteins in the blood and the urine as a diagnostic and screening tool for preeclampsia. The availability of a test to predict preeclampsia would be a powerful tool in preventing preeclampsia-induced mortality, especially in developing nations, where high-risk specialists are limited. This review will summarize our current understanding of the role of circulating angiogenic proteins in the pathogenesis and clinical diagnosis/prediction of preeclampsia.
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PMID:Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia. 1623 May 16

Preeclampsia is characterized by the clinical triad of new hypertension, proteinuria, and edema after 20 wk of gestation. Recent evidence suggests that disturbances in angiogenic factors (such as vascular endothelial growth factor and placental growth factor) signaling and endothelial health may play a major role in the pathogenesis of preeclampsia. Exogenous administration of soluble fms-like tyrosine kinase-1 (sFlt-1; a circulating anti-angiogenic protein) results in a preeclampsia-like phenotype in rats. This chapter describes the methods we use in our laboratory to create the sFlt-1 induced-rat model of preeclampsia.
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PMID:In vivo rat model of preeclampsia. 1651 96

Preeclampsia is a major cause of maternal and neonatal morbidity and mortality worldwide. Although the etiology of preeclampsia is still unclear, recent studies suggest that its major phenotypes, hypertension and proteinuria, may be due to an excess of circulating anti-angiogenic growth factors, most notably soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng). sFlt1 is an endogenous protein that is produced by the placenta. sFlt1 is able to bind to the angiogenic growth factors vascular endothelial growth factor and placental growth factor, thereby neutralizing their functions. High serum concentrations of sFlt1 and low concentrations of free vascular endothelial growth factor and free placental growth factor have been observed during and prior to clinical manifestation of preeclampsia. More recently, serum levels of sEng were also shown to be significantly elevated in preeclamptic women and levels of sEng correlated strongly with disease severity. Therefore, measurement of sFlt1 and sEng in the maternal circulation may be a useful diagnostic and screening tool for preeclampsia. The availability of such a test to predict preeclampsia would have significant impact on current obstetrical care and may help reduce preeclampsia-induced morbidity and mortality. This review will focus on the role of angiogenic factors in normal and abnormal placental development and indicate how measurement of circulating angiogenic factors may help identify women at risk of preeclampsia.
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PMID:Angiogenic factors and preeclampsia. 1712 49

Preeclampsia is a major cause of maternal, fetal and neonatal mortality worldwide. The mechanisms that initiate preeclampsia in humans have been elusive, but some parts of the puzzle have begun to come together. A key discovery in the field was the realization that its major phenotypes, such as hypertension and proteinuria, are due to excess circulating soluble fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1). sFlt-1 is an endogenous anti-angiogenic protein that is made by the placenta and acts by neutralizing the pro-angiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). More recently, soluble endoglin, another circulating anti-angiogenic protein was found to synergize with sFlt-1 and contribute to the pathogenesis of preeclampsia. Abnormalities in these circulating angiogenic proteins are not only present during clinical preeclampsia, but also antedate clinical symptoms by several weeks. This review will summarize our current understanding of the molecular mechanism of preeclampsia, with an emphasis on the recently characterized circulating anti-angiogenic proteins.
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PMID:Molecular mechanisms of preeclampsia. 1755 34

Several drugs currently in development target the vascular endothelial growth factor (VEGF) pathway, a validated target in the treatment of non-small cell lung cancer (NSCLC). Most clinical trial data generated to date have been with either bevacizumab, a monoclonal antibody to VEGF, or small-molecule inhibitors of VEGF receptor (VEGFR) tyrosine kinase activity (sunitinib, sorafenib, and ZD6474). VEGF Trap, an engineered soluble receptor made from extracellular domains of VEGFR1 and VEGFR2, binds to all isoforms of VEGF and to placental growth factor. VEGF Trap binds to VEGF-A and VEGF-B with markedly higher affinity than bevacizumab. The toxicities seen in phase I trials of s.c. and i.v. administration of VEGF Trap, hypertension and proteinuria, are similar to those seen with other molecules that target the VEGF pathway. In the s.c. VEGF Trap phase I trial, significant radiographic improvement was observed in a patient with heavily pretreated NSCLC. Ongoing phase I trials are evaluating combinations of VEGF Trap with platinum-based doublets and single-agent docetaxel. The activity of single-agent VEGF Trap in NSCLC is being assessed in a multicenter phase II trial.
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PMID:Vascular endothelial growth factor trap in non small cell lung cancer. 1767 Nov 53

Leptin, one of adipocytokines, plays a wide range of important roles in reproductive biology. We have previously reported that low hypo-adiponectinemia might be involved in the pathophysiology of overweight preeclampsia (PE) patients. Moreover, recent reports have underscored the importance of circulating angiogenic factors in the pathophysiology of PE. Here, we examined whether leptin in conjunction with adiponectin and/or angiogenic factors plays some role in the pathophysiology of PE. We performed a cross-sectional study in 34 PE patients and normal pregnancies matched for gestational age and body mass index as controls. We measured serum concentrations of leptin, adiponectin, the angiogenic factors vascular endothelial growth factor (VEGF), placental growth factor, and the soluble VEGF receptors sFlt-1 and sFlk-1. We observed that leptin levels in PE patients were significantly higher compared with those in controls, but did not observe significant differences between normal- and overweight patients in both groups. We also showed a significant negative correlation between leptin and adiponectin in controls, but not in PE patients. There was a significant correlation between leptin and sFlt-1 in PE patients, while there were significant differences of body mass index, mean blood pressure and proteinuria between high and low leptin/sFlt-1 ratio group in PE patients. Moreover, there was a significant difference of leptin level between IUGR and normal growth group in PE patients. These results suggest that the circulating increased leptin might be derived mainly from the placenta and regulated by the placental hypoxic condition, whereas adiponectin might be derived mainly from adipose tissue; and that leptin might play some role through insulin resistance, autonomic activation, or direct effect on endothelium with other angiogenic factors in pathophysiology of PE compared with the exaggerated release of adiponectin from adipose tissue.
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PMID:Circulating leptin and angiogenic factors in preeclampsia patients. 1849 Aug 35

Pre-eclampsia, a pregnancy complication characterized by hypertension and proteinuria, is still a major cause of neonatal and maternal mortality, and acute and long-term morbidities for both mother and neonate. There is mounting evidence that an imbalance between angiogenic factors, such as VEGF (vascular endothelial growth factor) or PlGF (placental growth factor), and factors inhibiting angiogenesis, such as sFlt1 (soluble fms-like tyrosine kinase 1) and sEng (soluble endoglin), are closely related to the pathogenesis of pre-eclampsia. In the present issue of Clinical Science, Bills and co-workers report that VEGF(165)b, an alternative splice variant of the VEGF pre-mRNA, is up-regulated in women with normal pregnancy and that this increase was delayed or diminished in women who developed pre-eclampsia. Thus this protein could serve (alone or in combination with other parameters) as a new marker for risk assessment in terms of pre-eclampsia.
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PMID:Angiogenic factors and pre-eclampsia: an early marker is needed. 1882 76


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