Preeclampsia is a complication of pregnancy with significant morbidity and mortality for the mother and the fetus. Presumptions are made that placental hypoxia has a causative role in the clinical syndrome. Furthermore, soluble fms-like tyrosine kinase 1 (sFLT-1) has been shown to have a role in the maternal syndrome of preeclampsia. We investigated the relationship between uteroplacental ischemia (UPI), the maternal clinical syndrome of preeclampsia and sFLT-1 in non-human primates. The induction of UPI in a pregnant non-human primate resulted in the development of a clinical entity analogous to human preeclampsia. This was illustrated by the increase in blood pressure, development of proteinuria, and renal histological changes identical to human preeclampsia. A significant elevation in the placental and peripheral blood mononuclear cell sFLT-1 mRNA expression was noted, translating to a significant elevation in circulating sFLT-1. Thus, this sequence suggests that a pathogenic reduction in placental perfusion results in the development of the maternal syndrome of preeclampsia and an increase in circulating sFLT-1, which is derived both from placental and extra-placental sources.
Placental growth factor (PlGF) is an increasingly important molecule in the prediction, diagnosis and treatment of pre-eclampsia. It has pro-angiogenic effects on the feto-placental circulation and supports trophoblast growth. Mechanisms by which PlGF expression is regulated continue to be investigated. Low circulating PlGF precedes the manifestation of clinical disease in pre-eclamptic pregnancies and intrauterine growth restriction. This suggests that low PlGF is a marker of abnormal placentation, but it remains uncertain whether this is a cause or consequence. Prediction of pre-eclampsia using PlGF is promising and may assist in the targeting of resources to women at highest risk of adverse pregnancy outcomes. Promisingly, experimental animal models of pre-eclampsia have been successfully treated with supplemental PlGF. Treatment of pre-eclampsia with PlGF is a potential therapeutic option requiring further exploration. This review focuses specifically on the role of PlGF in normal and pathological placental development and in the clinical management of pre-eclampsia.
Hypertensive disorders of pregnancy are associated with vascular dysfunction in the pregnancy and an increased risk of long-term cardiovascular disease (CVD) in the mother. What remains to be understood is whether the length, severity of the disease, the treatment of hypertension in pregnancy, or the subtype of hypertensive disorders of pregnancy are significant predictors of future CVD. We undertook a retrospective cohort study to review all women who gave birth at a tertiary hospital in Sydney between the years 1980 and 1989 (n=31 656). A cohort of women was further defined by having hypertension during the antenatal, intrapartum, or postnatal periods (n=4387). Randomly selected records of women (n=1158) with a hypertensive disorder of pregnancy were individually reviewed to collect data on their pregnancy and pregnancy outcomes. The entire cohort then underwent linkage analysis to future CVDs. Women who presented with gestational hypertension were at greater risk of future hypertension and ischemic heart disease compared with the women who were diagnosed with preeclampsia. There was no significant difference between the women who were treated with antihypertensive medication and the women who did not receive antihypertensive medication or the duration of hypertensive disorders of pregnancy and future admission for CVD, although severity of hypertension tracked with increased risk of future hypertension in all groups. This study demonstrated that all women who present with any of the subtypes of hypertensive disorders in pregnancy are at significant risk of future CVD compared with women who remain normotensive during their pregnancy.
Preeclampsia (PE) is a placentally-induced hypertensive disorder of pregnancy that is associated with significant morbidity and mortality to mothers and fetuses. Clinical manifestations of preterm PE result from excess circulating soluble vascular endothelial growth factor receptor FLT1 (sFLT1 or sVEGFR1) of placental origin. Here we identify short interfering RNAs (siRNAs) that selectively silence the three
sFLT1
mRNA isoforms primarily responsible for placental overexpression of sFLT1. Full chemical stabilization in the context of hydrophobic modifications enables productive siRNA accumulation in the placenta (up to 7% of injected dose) and reduces circulating sFLT1 in pregnant mice (up to 50%). In a baboon PE model, single dose of siRNAs suppressed sFLT1 overexpression and clinical signs of PE. Our results demonstrate RNAi-based extra-hepatic modulation of gene expression with non-formulated siRNAs in non-human primates and establish a path toward a new treatment paradigm for patients with preterm PE.
The protease fibroblast activation protein (FAP) is a specific marker of activated mesenchymal cells in tumour stroma and fibrotic liver. A specific, reliable FAP enzyme assay has been lacking. FAP's unique and restricted cleavage of the post proline bond was exploited to generate a new specific substrate to quantify FAP enzyme activity. This sensitive assay detected no FAP activity in any tissue or fluid of FAP gene knockout mice, thus confirming assay specificity. Circulating FAP activity was ∼20- and 1.3-fold less in baboon than in mouse and human plasma, respectively. Serum and plasma contained comparable FAP activity. In mice, the highest levels of FAP activity were in uterus, pancreas, submaxillary gland and skin, whereas the lowest levels were in brain, prostate, leukocytes and testis. Baboon organs high in FAP activity included skin, epididymis, bladder, colon, adipose tissue, nerve and tongue. FAP activity was greatly elevated in tumours and associated lymph nodes and in fungal-infected skin of unhealthy baboons. FAP activity was 14- to 18-fold greater in cirrhotic than in non-diseased human liver, and circulating FAP activity was almost doubled in alcoholic cirrhosis. Parallel DPP4 measurements concorded with the literature, except for the novel finding of high DPP4 activity in bile. The new FAP enzyme assay is the first to be thoroughly characterised and shows that FAP activity is measurable in most organs and at high levels in some. This new assay is a robust tool for specific quantitation of FAP enzyme activity in both preclinical and clinical samples, particularly liver fibrosis.
The effectiveness of continuous positive airway pressure in improving fetal movements suggests a pathogenetic role for sleep disordered breathing in the reduced fetal activity and possibly in the poorer fetal outcomes associated with preeclampsia.
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