Preeclampsia: a link between trophoblast dysregulation and an antiangiogenic state

Romero, Roberto; Chaiworapongsa, Tinnakorn

doi:10.1172/jci70431

Cited by 112 publications

(73 citation statements)

References 49 publications

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“…These proteins are involved in angiogenesis (e.g., PlGF), coagulation (e.g., tissue factor), cell division (e.g., RAs-related Nuclear protein), and cell-to-cell interaction (e.g., tyrosine-protein kinase Fer). The finding that, after 22 weeks of gestation, PlGF is the best predictor of late-onset preeclampsia, especially in its more severe form, is consistent with previous reports [61,115,170–173]. We and others [55,70,174] presented the use of this angiogenic factor as a tool for the assessment of the impending risk for preeclampsia, demonstrating lower concentrations of PlGF in cases when compared to controls as early as at least six weeks prior to the onset of the disease [61].…”

Section: Discussionsupporting

confidence: 92%

The prediction of late-onset preeclampsia: Results from a longitudinal proteomics study

et al. 2017

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BackgroundLate-onset preeclampsia is the most prevalent phenotype of this syndrome; nevertheless, only a few biomarkers for its early diagnosis have been reported. We sought to correct this deficiency using a high through-put proteomic platform.MethodsA case-control longitudinal study was conducted, including 90 patients with normal pregnancies and 76 patients with late-onset preeclampsia (diagnosed at ≥34 weeks of gestation). Maternal plasma samples were collected throughout gestation (normal pregnancy: 2–6 samples per patient, median of 2; late-onset preeclampsia: 2–6, median of 5). The abundance of 1,125 proteins was measured using an aptamers-based proteomics technique. Protein abundance in normal pregnancies was modeled using linear mixed-effects models to estimate mean abundance as a function of gestational age. Data was then expressed as multiples of-the-mean (MoM) values in normal pregnancies. Multi-marker prediction models were built using data from one of five gestational age intervals (8–16, 16.1–22, 22.1–28, 28.1–32, 32.1–36 weeks of gestation). The predictive performance of the best combination of proteins was compared to placental growth factor (PIGF) using bootstrap.Results1) At 8–16 weeks of gestation, the best prediction model included only one protein, matrix metalloproteinase 7 (MMP-7), that had a sensitivity of 69% at a false positive rate (FPR) of 20% (AUC = 0.76); 2) at 16.1–22 weeks of gestation, MMP-7 was the single best predictor of late-onset preeclampsia with a sensitivity of 70% at a FPR of 20% (AUC = 0.82); 3) after 22 weeks of gestation, PlGF was the best predictor of late-onset preeclampsia, identifying 1/3 to 1/2 of the patients destined to develop this syndrome (FPR = 20%); 4) 36 proteins were associated with late-onset preeclampsia in at least one interval of gestation (after adjustment for covariates); 5) several biological processes, such as positive regulation of vascular endothelial growth factor receptor signaling pathway, were perturbed; and 6) from 22.1 weeks of gestation onward, the set of proteins most predictive of severe preeclampsia was different from the set most predictive of the mild form of this syndrome.ConclusionsElevated MMP-7 early in gestation (8–22 weeks) and low PlGF later in gestation (after 22 weeks) are the strongest predictors for the subsequent development of late-onset preeclampsia, suggesting that the optimal identification of patients at risk may involve a two-step diagnostic process.

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Section: Discussionsupporting

confidence: 92%

The prediction of late-onset preeclampsia: Results from a longitudinal proteomics study

et al. 2017

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“…The placenta is both necessary and sufficient to cause the disease, and delivery of the placenta is the only treatment (Powe et al 2011). Over the last decade, preeclampsia has been recognized as an antiangiogenic state (Romero and Chaiworapongsa 2013). Excessive placental production of antiangiogenic factors sFlt-1 and sEng are liberated into the maternal circulation inducing the clinical syndrome.…”

Section: Pathogenesis Angiogenic Factors As Mediators Of the Maternalmentioning

confidence: 99%

“…Importantly, angiogenic factors are also essential for maintenance of normal vessel health; they provide important cues for organ development. Increased levels of the antiangiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble Endoglin (sEng) trap circulating vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and transforming growth factor b (TGFb) respectively, decreasing their free levels, leading to endothelial dysfunction and the clinical manifestations of the disease (Maynard et al 2003;Levine et al 2004Levine et al , 2006bVenkatesha et al 2006;Romero and Chaiworapongsa 2013). Interestingly, the preeclampsia-like signs and symptoms are also seen in cancer patients receiving antiangiogenic chemotherapy (Hurwitz et al 2004;Patel et al 2008;Vigneau et al 2014).…”

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confidence: 99%

Molecular Mechanisms of Preeclampsia

Cerdeira

2015

Cold Spring Harb Perspect Med

158

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Preeclampsia is a pregnancy-specific disease characterized by new onset hypertension and proteinuria after 20 wk of gestation. It is a leading cause of maternal and fetal morbidity and mortality worldwide. Exciting discoveries in the last decade have contributed to a better understanding of the molecular basis of this disease. Epidemiological, experimental, and therapeutic studies from several laboratories have provided compelling evidence that an antiangiogenic state owing to alterations in circulating angiogenic factors leads to preeclampsia. In this review, we highlight the role of key circulating antiangiogenic factors as pathogenic biomarkers and in the development of novel therapies for preeclampsia.

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“…8 It has therefore been hypothesized that excessive production of both anti-angiogenic proteins sFlt1 (inhibiting VEGF & PlGF signaling) and soluble endoglin, (inhibiting TGF-beta signaling) may lead to endothelial dysfunction, and the manifestations of human preeclampsia, and that phenotypic preeclampsia is due to an anti-angiogenic state. 9, 10 …”

Section: Introductionmentioning

confidence: 99%