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1.  An Imbalance between Angiogenic and Anti-angiogenic Factors precedes Fetal Death in a subset of patients: Results of a Longitudinal Study 
OBJECTIVE
Fetal death at the time of diagnosis has higher maternal plasma concentrations of the anti-angiogenic factor, soluble vascular endothelial growth factor receptor (sVEGFR)-1, than that of women with normal pregnancy. An important question is whether these changes are the cause or consequence of fetal death. To address this issue, we conducted a longitudinal nested case-control study and measured the maternal plasma concentrations of selective angiogenic and anti-angiogenic factors before the diagnosis of a fetal death. The anti-angiogenic factors studied included sVEGFR-1, soluble endoglin (sEng), and the angiogenic factor, placental growth factor (PlGF).
Methods
A retrospective longitudinal nested case-control study was conducted. It included 143 singleton pregnancies in the following groups: (1) patients with uncomplicated pregnancies who delivered a term infant with an appropriate weight for gestational age (n=124); and (2) patients who had a fetal death (n=19). Samples were collected at each prenatal visit, scheduled at 4-week intervals from the first trimester until delivery. Plasma concentrations of sVEGFR-1, sEng, and PlGF were determined by specific and sensitive ELISA. A linear mixed-effects model was used for analysis.
Results
1) Linear mixed-effects model analyses indicated that the average profiles of analyte concentrations as a function of gestational age for sVEGFR-1, sEng and PlGF were different between women destined to have a fetal death and those with normal pregnancy outcome after adjusting for covariates (p<0.05); 2) Plasma sVEGFR-1 concentrations in patients destined to have a fetal death were significantly lower between 7 and 11 weeks of gestation and became significantly higher than those of women with a normal pregnancy between 23 and 35 weeks of gestation (p<0.05); 3) Similarly, plasma sEng concentrations of women destined to have a fetal death were lower at 7 weeks of gestation (p=0.04) and became significantly higher than those of women destined to have a normal pregnancy between 23 and 41 weeks of gestation (p<0.05); 4) In contrast, plasma PlGF concentrations were higher among patients destined to develop a fetal death between 7 and 13 weeks of gestation and became significantly lower than those in the control group between 22 and 40 weeks of gestation (p<0.05); 5) The ratio of PlGF/sVEGFR-1 x sEng was significantly higher in women destined to have a fetal death between 7 and 13 weeks of gestation (89%–765%) and significantly lower (45%–76%) than those in normal pregnant women between 20 and 41 weeks of gestation (p<0.05); 6) Similar results were obtained when patients with a fetal death were stratified into those who were diagnosed before or after 37 weeks.
Conclusions
1) Patient destined to have a fetal death, compared to normal pregnancy, was characterized by higher plasma concentrations of PlGF during the first trimester, and this profile changed into an anti-angiogenic one during the second and third trimesters.
doi:10.3109/14767051003681121
PMCID: PMC3023956  PMID: 20459337
soluble VEGF receptor-1 (sVEGFR-1); sFlt-1; soluble endoglin (sEng); placental growth factor (PLGF); mixed- effect model; fetal demise; stillbirth; pregnancy; anti-angiogenic state
2.  Circulating Soluble Endoglin Levels in Pregnant Women in Cameroon and Malawi—Associations with Placental Malaria and Fetal Growth Restriction 
PLoS ONE  2011;6(9):e24985.
Placental infections with Plasmodium falciparum are associated with fetal growth restriction resulting in low birth weight (LBW). The mechanisms that mediate these effects have yet to be completely described; however, they are likely to involve inflammatory processes and dysregulation of angiogenesis. Soluble endoglin (sEng), a soluble receptor of transforming growth factor (TGF)-β previously associated with preeclampsia in pregnant women and with severe malaria in children, regulates the immune system and influences angiogenesis. We hypothesized that sEng may play a role in development of LBW associated with placental malaria (PM). Plasma levels of sEng were measured in women (i) followed prospectively throughout pregnancy in Cameroon (n = 52), and (ii) in a case-control study at delivery in Malawi (n = 479). The relationships between sEng levels and gravidity, peripheral and placental parasitemia, gestational age, and adverse outcomes of PM including maternal anemia and LBW were determined. In the longitudinal cohort from Cameroon, 28 of 52 women (54%) experienced at least one malaria infection during pregnancy. In Malawi we enrolled two aparasitemic gravidity-matched controls for every case with PM. sEng levels varied over the course of gestation and were significantly higher in early and late gestation as compared to delivery (P<0.006 and P<0.0001, respectively). Circulating sEng levels were higher in primigravidae than multigravidae from both Cameroon and Malawi, irrespective of malarial infection status (p<0.046 and p<0.001, respectively). Peripheral parasitemia in Cameroonian women and PM in Malawian women were each associated with elevated sEng levels following correction for gestational age and gravidity (p = 0.006 and p = 0.033, respectively). Increased sEng was also associated with the delivery of LBW infants in primigravid Malawian women (p = 0.017); the association was with fetal growth restriction (p = 0.003) but not pre-term delivery (p = 0.286). Increased circulating maternal sEng levels are associated with P. falciparum infection in pregnancy and with fetal growth restriction in primigravidae with PM.
doi:10.1371/journal.pone.0024985
PMCID: PMC3178568  PMID: 21966395
3.  Plasma Concentrations of Soluble Endoglin versus Standard Evaluation in Patients with Suspected Preeclampsia 
PLoS ONE  2012;7(10):e48259.
Background
The purpose of this study was to compare plasma soluble endoglin (sEng) levels with standard clinical evaluation or plasma levels of other angiogenic proteins [soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF)] in predicting short-term adverse maternal and perinatal outcomes in women with suspected preeclampsia presenting prior to 34 weeks.
Methods and Findings
Data from all women presenting at <34 weeks for evaluation of preeclampsia with singleton pregnancies (July 2009−October 2010) were included in this analysis and sEng levels were measured at presentation. Data was analyzed for 170 triage encounters and presented as median {25−75th centile}. Thirty-three percent of patients (56 of 170) experienced an adverse outcome. sEng levels (ng/ml) were significantly elevated in patients who subsequently experienced adverse outcomes compared to those who did not (32.3 {18.1, 55.8} vs 4.8 {3.2, 8.6}, p<0.0001). At a 10% false positive rate, sEng had higher detection rates of adverse outcomes than the combination of highest systolic blood pressure, proteinuria and abnormal laboratory tests (80.4 {70.0, 90.8} vs 63.8 {51.4, 76.2}, respectively). Subjects in the highest quartile of sEng were more likely to deliver early compared to those in the lowest quartile (HR: 14.96 95% CI: 8.73−25.62, p<0.0001). Natural log transformed sEng correlated positively with log sFlt1 levels (r = 0.87) and inversely with log PlGF levels (r = −0.79) (p<0.0001 for both). Plasma sEng had comparable area under the curve for prediction of adverse outcomes as measurement of sFlt1/PlGF ratio (0.88 {0.81, 0.95} for sEng versus 0.89 {0.83, 0.95} for sFlt1/PlGF ratio, p = 0.74).
Conclusions
In women with suspected preeclampsia presenting prior to 34 weeks of gestation, sEng performs better than standard clinical evaluation in detecting adverse maternal and fetal outcomes occurring within two weeks of presentation. Soluble endoglin was strongly correlated with sFlt1 and PlGF levels, suggesting common pathogenic pathways leading to preeclampsia.
doi:10.1371/journal.pone.0048259
PMCID: PMC3482204  PMID: 23110221
4.  Evidence of an Imbalance of Angiogenic/Anti-angiogenic Factors in Massive Perivillous Fibrin Deposition (Maternal Floor Infarction): a Placental Lesion associated with Recurrent Miscarriage and Fetal Death 
American journal of obstetrics and gynecology  2013;208(4):310.e1-310.e11.
Objective
Massive perivillous fibrin deposition (MPFD) is associated with serious complications of pregnancy including recurrent spontaneous abortion, fetal growth restriction and fetal demise. The aim of the study was to determine if maternal plasma concentrations of angiogenic/anti-angiogenic factors in MPFD differ from uncomplicated pregnancies.
Study Design
This retrospective longitudinal case-control study included MPFD cases (n=10) and control patients (n=175) with uncomplicated pregnancies who were enrolled in a longitudinal study and delivered at term. Serial plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor (sVEGFR) -1 and -2 were determined by ELISA (cases, n=28 samples; controls, n=751 samples). Individual analyte concentrations were averaged across gestational length at specimen collection intervals. Linear mixed models were used to test for differences in log transformed mean analyte concentrations both overall and as a function of time.
Results
1) Patients with MPFD had a lower mean plasma PlGF concentration (p=0.03) and higher mean plasma concentrations of sVEGFR-1 and sEng (both p<0.01) than controls, adjusted for potential confounders; 2) the mean plasma concentration of PlGF differed further among cases and controls as a function of gestational age interval (p<0.0001); however, mean sVEGFR-1 and sEng group differences as a function of gestational age interval approached but did not reach significance (p=0.09, p=0.11, respectively); 3) patients with MPFD had lower mean plasma concentrations of PlGF/sVEGFR-1 (p<0.0001) and PlGF/sEng (p<0.001); both of these relationships differed further as a function of gestational age interval (both p<0.0001); and 4) differences in mean sVEGFR-1, sEng, and the ratios of PlGF/sVEGFR-1 and PlGF/sEng were observed before 20 weeks of gestation.
Conclusion
An imbalance of angiogenic/anti-angiogenic factors is present in patients with MPFD prior to the diagnosis. We propose that these changes participate in the mechanisms responsible for adverse pregnancy outcomes in patients with MPFD.
doi:10.1016/j.ajog.2013.01.017
PMCID: PMC3939787  PMID: 23333548
maternal floor infarction; recurrent pregnancy loss; flt-1; soluble vascular endothelial growth factor; placental growth factor; soluble endoglin
5.  Acute Pyelonephritis during Pregnancy Changes the Balance of Angiogenic and Anti-Angiogenic Factors in Maternal Plasma 
Objective
Angiogenic factors have been implicated in the pathophysiology of sepsis. In experimental models of sepsis (endotoxemia and/or cecal ligation puncture), there is increased expression of vascular endothelial growth factors (VEGF) and the administration of exogenous soluble VEGF receptor (sVEGFR)-1, an antagonist to VEGF, reduces morbidity and mortality. Moreover, a dramatic elevation in sVEGFR-1 has been demonstrated in human sepsis. Although a balance between angiogenic and anti-angiogenic factors is essential for feto-placental development, the changes of angiogenic factors during pregnancy in the context of infection have never been explored. Angiogenic factors also play crucial roles in the pathophysiology of preeclampsia. This study was conducted to determine if maternal plasma concentrations of placental growth factor (PlGF), sVEGFR-2 and soluble endoglin (sEng) change in pregnancies complicated by acute pyelonephritis (AP) compared to normal pregnancy and preeclampsia (PE).
Study Design
A case-control study was conducted in patients with AP, normal pregnant women (NP) and patients with PE (n=36 for each group) matched for gestational age. AP was diagnosed in the presence of fever (temperature ≥ 38°C), clinical signs of infection, and a positive urine culture for micro-organisms. Plasma concentrations of PlGF, sVEGFR-2 and sEng were determined by ELISA. The results of plasma sVEGFR-1 concentrations has previously been reported before, but were included in this study to provide a complete picture of the angiogenic/anti-angiogenic profiles. Serum concentrations of interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, interferon (IFN)-γ, Granulocyte macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-α were also determined using high sensitivity multiplexed immunoassays in patients with AP and NP.
Results
AP was associated with a lower median plasma concentration of PlGF and sVEGFR-2 than NP (both p<0.001). There were no significant differences in the median plasma concentrations of sEng and sVEGFR-1 between AP and NP (p=0.7 and 0.5 respectively). In contrast, there was a 5-fold decrease of the median plasma concentration of PlGF, and an 8-10 fold increase of the median plasma concentrations of sVEGFR-1 and sEng in PE compared to those in AP (all p<0.001). No significant difference in the median plasma concentration of sVEGFR-2 was observed between patients with PE and AP (p=0.5). Pregnant women with acute pyelonephritis had median plasma concentrations of IL-6, IL-7, IL-8, IL-10, IFN-γ, and TNF-α significantly higher than those in normal pregnant women (all p<0.001, except IL-7 p=0.004).
Conclusion
AP is associated with changes in the profile of angiogenic and anti-angiogenic factors. Although some of these changes resemble those in PE (decreased PlGF and sVEGFR-2), the magnitude of the changes of PlGF is much higher in PE. We conclude that despite high plasma inflammatory cytokine concentrations, acute systemic inflammation in pregnancy has a different angiogenic/anti-angiogenic profile than that of preeclampsia.
PMCID: PMC3471211  PMID: 20213923
preeclampsia; angiogenesis; angiogenic factor; acute pyelonephritis; cytokines; systemic inflammation; infection; inflammation
6.  Effect of Antihypertensive Therapy with Alpha Methyldopa on Levels of Angiogenic Factors in Pregnancies with Hypertensive Disorders 
PLoS ONE  2008;3(7):e2766.
Background
Antihypertensive drugs are believed to lower blood pressure in pre-eclampsia by direct or central vasodilatory mechanisms. However, they could also act by decreasing production of anti-angiogenic proteins involved in the pathophysiology of hypertension and proteinuria in pre-eclampsia (PE). The aim of our study was to evaluate the impact of antihypertensive therapy with alpha methyldopa on maternal circulating levels and placental production of soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng), vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in hypertensive disorders of pregnancy.
Methodology/Principal Findings
In a study conducted at University College Hospital and the Homerton University Hospital in London, we recruited 51 women with PE, 29 with gestational hypertension (GH), and 80 matched normotensive controls. Eight (16%) of the women with PE had severe disease. Placental samples were obtained from a further 48 women (14 PE, 10 GH and 24 matched controls). Serum levels of angiogenic factors were measured before and 24–48 hours after commencing antihypertensive therapy with alpha methyldopa for clinical indications. The same parameters were measured in placental extracts. In both PE (P<0.0001) and GH (P<0.05), serum sFlt-1 was increased and PlGF reduced at all gestations (P<0.001) compared to controls. Serum sEng levels were also increased in PE. Placental concentration of sFlt-1 and sEng was significantly higher in women with PE compared to controls and women with GH (P<0.0001). The concentration of PlGF was significantly lower in the placental tissue of women with PE compared to GH (P = 0.008). Antihypertensive treatment was associated with a significant fall in serum and placental content of sFlt1 and sEng in PE only.
Conclusions
Our data suggest that alpha methyldopa may have a specific effect on placental and/or endothelial cell function in pre-eclampsia patients, altering angiogenic proteins.
doi:10.1371/journal.pone.0002766
PMCID: PMC2447877  PMID: 18648513
7.  Circulating anti-angiogenic factors during hypertensive pregnancy and increased risk of respiratory distress syndrome in preterm neonates 
OBJECTIVE
To test the hypothesis that high circulating concentrations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS).
STUDY DESIGN
This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hypertension and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor [PlGF] and soluble endoglin [sEng] in maternal serum were measured at 21–32 weeks of gestation.
RESULTS
Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5 % versus 20.9%, P=0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% C.I. 1.08, 4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during mid-pregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL versus 7,000 pg/mL, P = 0.01).
CONCLUSIONS
Preterm preeclampsia and gestational hypertension, characterized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during mid-pregnancy were substantially higher in women whose infants developed RDS.
doi:10.3109/14767058.2011.640368
PMCID: PMC3414194  PMID: 22097923
anti-angiogenic; soluble fms-like tyrosine kinase 1; sVEGF R1; sFlt1; placental growth factor; PlGF; soluble endoglin; sEng; respiratory distress syndrome; RDS; neonate; preterm; preeclampsia; gestational hypertension
8.  Unexplained Fetal Death is Associated with Increased Concentrations of Anti-Angiogenic Factors in Amniotic Fluid 
Objective
Angiogenesis is critical for successful pregnancy. An anti-angiogenic state has been implicated in preeclampsia, fetal growth restriction and fetal death. Increased maternal plasma concentrations of the anti-angiogenic factor, soluble vascular endothelial growth factor receptor (sVEGFR)-1, have been reported in women with preeclampsia and in those with fetal death. Recent observations indicate that an excess of sVEGFR-1 and soluble endoglin (sEng) is also present in the amniotic fluid of patients with preeclampsia. The aim of this study was to determine if fetal death is associated with changes in amniotic fluid concentrations of sVEGFR-1 and sEng, two powerful anti-angiogenic factors.
Study Design
This cross-sectional study included patients with fetal death (n=35) and controls (n=129). Fetal death was subdivided according to clinical circumstances into: 1) unexplained (n=25); 2) preeclampsia and/or placental abruption (n=5); and 3) chromosomal/congenital anomalies (n=5). The control group consisted of patients with preterm labor (PTL) who delivered at term (n=92) and women at term not in labor (n=37). AF concentrations of sVEGFR-1 and sEng were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied.
Results
1) Patients with a fetal death had higher median amniotic fluid concentrations of sVEGFR-1 and sEng than women in the control group (p<0.001 for each); 2) these results remained significant among different subgroups of stillbirth (p<0.05 for each); and 3) amniotic fluid concentrations of sVEGFR-1 and those of sEng above the 3rd quartile were associated with a significant risk of unexplained preterm fetal death (adjusted OR = 10.8; 95%CI 1.3-89.2 and adjusted OR 87; 95% CI 2.3-3,323, respectively).
Conclusion
Patients with an unexplained fetal death at diagnosis are characterized by an increase in the amniotic fluid concentrations of sVEGFR-1 and sEng. These observations indicate that an excess of anti-angiogenic factors in the amniotic cavity is associated with unexplained fetal death especially in preterm gestations.
doi:10.3109/14767050903443467
PMCID: PMC3016945  PMID: 20199197
angiogenic factor; soluble vascular endothelial growth factor receptor-1; sFlt-1; soluble endoglin; stillbirth; fetal demise; preeclampsia; congenital anomalies
9.  The Effect of Immune Factors, Tumor Necrosis Factor-α (TNF-α), and Agonistic Autoantibodies to the Angiotensin II Type I Receptor (AT1-AA) on Soluble fms-Like Tyrosine-1 (sFlt-1) and Soluble Endoglin (sEng) Production in Response to Hypertension During Pregnancy 
American journal of hypertension  2010;23(8):911-916.
BACKGROUND
Preeclampsia is considered a disease of immunological origin associated with abnormalities in inflammatory cytokines, tumor necrosis factor-α (TNF-α), and activated lymphocytes secreting AT1-AA. Recent studies have also demonstrated that an imbalance of angiogenic factors, soluble fms-like tyrosine kinase (sFlt-1), and sEndoglin, exists in preeclampsia; however, the mechanisms that initiate their overproduction are unclear.
METHODS
To determine the role of immune regulation of these factors, circulating and placental sFlt-1 and/or sEndoglin was examined from pregnant rats chronically treated with TNF-α or AT1-AA. On day 19 of gestation blood pressure was analyzed and serum and tissues were collected. Placental villous explants were excised and cultured on matrigel coated inserts for 24 h and sFlt-1 and sEndoglin was measured from media.
RESULTS
In response to TNF-α-induced hypertension, sFlt-1 increased from 180 ± 5 to 2,907 ± 412 pg/ml. sFlt-1 was also increased from cultured placental explants of TNF-α induced hypertensive pregnant rats (n = 12) (2,544 ± 1,132 pg/ml) vs. explants from normal pregnant (NP) rats (n = 12) (2,189 ± 586 pg/ml) where as sEng was undetectable. Circulating sFlt-1 increased from 245 ± 38 to 3,920 ± 798 pg/ml in response to AT1-AA induced hypertension. sFlt-1 levels were higher (3,400 ± 350 vs. 2,480 ± 900 pg/ml) in placental explants from AT1-AA infused rats (n = 12) than NP rats (n = 7). In addition, sEndoglin increased from 30 ± 2.7 to 44 ± 3.3 pg/ml (P < 0.047) in AT1-AA infused rats but was undetectable in the media of the placental explants.
CONCLUSIONS
These data suggest that immune factors may serve as an important stimulus for both sFlt-1 and sEndoglin production in response to placental ischemia.
doi:10.1038/ajh.2010.70
PMCID: PMC3500852  PMID: 20431529
antiangiogenic factors; blood pressure; hypertension; immune activation; pregnancy
10.  MATERNAL PLASMA CONCENTRATIONS OF ANGIOGENIC/ANTI-ANGIOGENIC FACTORS IN THE THIRD TRIMESTER OF PREGNANCY TO IDENTIFY THE PATIENT AT RISK FOR STILLBIRTH AT OR NEAR TERM AND SEVERE LATE PREECLAMPSIA 
American journal of obstetrics and gynecology  2013;208(4):287.e1-287.e15.
OBJECTIVE
To determine if maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) at 30–34 weeks can identify mothers at risk for preeclampsia (PE), stillbirth and small-for-gestational-age neonates (SGA).
STUDY DESIGN
A prospective cohort study included 1269 singleton pregnant women who had blood samples obtained at 30–34 weeks and delivered after 34 weeks of gestation. Plasma concentrations of PlGF, sEng, and sVEGFR-1 were determined by ELISA.
RESULTS
The prevalence of late (>34 weeks) PE, severe late PE, stillbirth and SGA was 3.2% (n=40), 1.8% (n=23), 0.4% (n=5) and 8.5% (n=108), respectively. A plasma concentration of PlGF/sEng <0.3 MoM was associated with severe late PE [adjusted odds ratio (aOR) 16]; addition of PlGF/sEng to clinical risk factors increased the area under the ROC curve (AUC) from 0.76 to 0.88 (p=0.03). The ratio of PlGF/sEng or PlGF/sVEGFR-1 in the third trimester outperformed those obtained in the first or second trimester and uterine artery Doppler velocimetry at 20–25 weeks for the prediction of severe late PE (comparison of AUC; each p≤0.02). Both PlGF/sEng and PlGF/sVEGFR-1 ratios achieved a sensitivity of 74% with a fixed false positive rate of 15% for the identification of severe late PE. A plasma concentration of PlGF/sVEGFR-1 <0.12 MoM at 30–34 weeks had a sensitivity of 80%, a specificity of 94%, and a likelihood ratio of a positive test of 14 for the identification of subsequent stillbirth. Similar findings (sensitivity 80% and specificity 93%) were observed in a separate case-control study. Integrating these biomarkers with clinical data did not improve the prediction of SGA.
CONCLUSIONS
Risk assessment for severe late PE and stillbirth in the third trimester is possible with the determination of maternal plasma concentrations of angiogenic and anti-angiogenic factors at 30–34 weeks of gestation.
doi:10.1016/j.ajog.2013.01.016
PMCID: PMC4086897  PMID: 23333542
fetal death; placental growth factor (PlGF); soluble endoglin (sEng); soluble vascular endothelial growth factor receptor-1 (sVEGFR-1); severe preeclampsia; SGA
11.  Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population? 
Objective
To determine if change in maternal angiogenic biomarkers between the first and second trimesters predicts pre-eclampsia in low-risk nulliparous women.
Design
A nested case–control study of change in maternal plasma soluble Flt-1 (sFlt-1), soluble endoglin (sEng) and placenta growth factor (PlGF). We studied 158 pregnancies complicated by pre-eclampsia and 468 normotensive nonproteinuric controls.
Setting
A multicentre study in 16 academic medical centres in the USA.
Population
Low-risk nulliparous women.
Methods
Luminex assays for PlGF, sFlt-1 and sEng performed on maternal EDTA plasma collected at 9–12, 15–18 and 23–26 weeks of gestation. Rate of change of analyte between first and either early or late second trimester was calculated with and without adjustment for baseline clinical characteristics.
Main outcome measures
Change in PlGF, sFlt-1 and sEng.
Results
Rates of change of PlGF, sEng and sFlt-1 between first and either early or late second trimesters were significantly different in women who developed pre-eclampsia, severe pre-eclampsia or early-onset pre-eclampsia compared with women who remained normotensive. Inclusion of clinical characteristics (race, body mass index and blood pressure at entry) increased sensitivity for detecting severe and particularly early-onset pre-eclampsia but not pre-eclampsia overall. Receiver operating characteristics curves for change from first to early second trimester in sEng, PlGF and sFlt-1 with clinical characteristics had areas under the curve of 0.88, 0.84 and 0.86, respectively, and for early-onset pre-eclampsia with sensitivities of 88% (95% CI 64–99%), 77% (95% CI 50–93%) and 77% (95%CI 50–93%) for 80% specificity, respectively. Similar results were seen in the change from first to late second trimester.
Conclusion
Change in angiogenic biomarkers between first and early second trimester combined with clinical characteristics has strong utility for predicting early-onset pre-eclampsia.
doi:10.1111/1471-0528.12128
PMCID: PMC4104359  PMID: 23331974
Angiogenesis; endoglin; platelet growth factor; pre-eclampsia; sFlt-1
12.  Effect of Smoking on Circulating Angiogenic Factors in High Risk Pregnancies 
PLoS ONE  2010;5(10):e13270.
Objective
Changes in maternal concentrations of the anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), and the pro-angiogenic placental growth factor (PlGF) precede the development of preeclampsia in healthy women. The risk of preeclampsia is reduced in women who smoke during pregnancy. The objective of this study was to investigate whether smoking affects concentrations of angiogenic factors (sFlt1, PlGF, and sEng) in women at high risk for developing preeclampsia.
Study Design
We performed a secondary analysis of serum samples from 993 high-risk women (chronic hypertension, diabetes, multifetal gestation, and previous preeclampsia) in a preeclampsia prevention trial. sFlt1, sEng and PlGF were measured in serum samples obtained at study entry, which was prior to initiation of aspirin (median 19.0 weeks' [interquartile range of 16.0–22.6 weeks']). Smoking status was determined by self-report.
Results
sFlt1 was not significantly different in smokers from any high-risk groups compared to their nonsmoking counterparts. PlGF was higher among smokers compared to nonsmokers among diabetic women (142.7 [77.4–337.3] vs 95.9 [48.5–180.7] pg/ml, p = 0.005) and women with a history of preeclampsia (252.2 [137.1–486.0] vs 152.2 [73.6–253.7] pg/ml, p = 0.001). sEng was lower in smokers with multifetal gestations (5.8 [4.6–6.5] vs 6.8 [5.5–8.7] ng/ml, p = 0.002) and trended lower among smokers with diabetes (4.9 [3.8–5.6] vs 5.3 [4.3–6.3] ng/ml, p = 0.05). Smoking was not associated with a lower incidence of preeclampsia in any of these groups.
Conclusions
In certain high-risk groups, smoking is associated with changes in the concentrations of these factors towards a pro-angiogenic direction during early pregnancy; however, there was no apparent association between smoking and the development of preeclampsia in our cohort.
doi:10.1371/journal.pone.0013270
PMCID: PMC2953508  PMID: 20967275
13.  Soluble fms-Like Tyrosine Kinase 1 (sFlt1), Endoglin and Placental Growth Factor (PlGF) in Preeclampsia among High Risk Pregnancies 
PLoS ONE  2010;5(10):e13263.
Background
Differences in circulating concentrations of antiangiogenic factors sFlt1 and soluble endoglin (sEng) and the pro-angiogenic growth factor PlGF are reported to precede the onset of preeclampsia weeks to months in low-risk pregnant women. The objective of this study was to investigate whether similar changes can be detected in pregnant women at high-risk to develop the syndrome.
Methods
This study is a secondary analysis of the NICHD MFMU trial of aspirin to prevent preeclampsia in high-risk pregnancies. Serum samples were available from 194 women with pre-existing diabetes, 313 with chronic hypertension, 234 with multifetal gestation, and 252 with a history of preeclampsia in a previous pregnancy. Samples collected across pregnancy were analyzed in a blinded fashion for sFlt1, sEng and PlGF.
Results
The odds of developing preeclampsia were significantly increased among women with multiple fetuses for each 2-fold elevation in sFlt1, sEng and the ratio of angiogenic factors (e.g. OR 2.18, 95% CI 1.46-3.32), and significantly decreased for each 2-fold elevation in circulating PlGF (OR 0.50, 95% CI 0.30-0.82) between 7 and 26 weeks' gestation. Cross-sectional analysis of the angiogenic factors across gestation showed significant differences during the third trimester in women who develop preeclampsia compared with appropriate controls in all high-risk groups. However, when data were examined in relation to the gestational week when preeclampsia was diagnosed only sFlt1 was significantly higher 2 to 5 weeks before the clinical onset of preeclampsia and only in women with previous preeclampsia.
Conclusions
The pattern of elevated concentrations of sFlt1 and sEng, and low PlGF in high-risk pregnant subjects who develop preeclampsia is similar to that reported in low-risk pregnant women. However, differences in these factors among high-risk women who do and do not develop preeclampsia are modest, and do not appear to be clinically useful predictors in these high-risk pregnant women.
doi:10.1371/journal.pone.0013263
PMCID: PMC2952583  PMID: 20948996
14.  LATE-ONSET PREECLAMPSIA IS ASSOCIATED WITH AN IMBALANCE OF ANGIOGENIC AND ANTI-ANGIOGENIC FACTORS IN PATIENTS WITH AND WITHOUT PLACENTAL LESIONS CONSISTENT WITH MATERNAL UNDERPERFUSION 
Objective
An imbalance between maternal angiogenic/anti-angiogenic factors concentrations has been observed in preeclampsia (PE) and other obstetrical syndromes. However, the frequency of pathologic findings in the placenta and the changes in maternal plasma angiogenic/anti-angiogenic factor concentrations differ between late-and early-onset PE. The aim of this study was to determine if the maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor-1 and 2 (sVEGFR-1 and sVEGFR-2) are different in late-onset PE with and without placental pathologic findings consistent with maternal underperfusion.
Study design
A cross-sectional study was conducted including 64 uncomplicated women and 66 women with late-onset PE (>34 weeks) who had blood samples and placenta available for pathologic examination. Patients with late-onset PE were divided into those with and without placental histologic findings consistent with maternal underperfusion as proposed by the Society for Pediatric Pathology. Maternal plasma concentrations of PlGF, sEng, sVEGFR-1 and sVEGFR-2 were determined by ELISA. Non-parametric statistics were used for analysis.
Results
1) the prevalence of placental histological findings consistent with maternal underperfusion among women with late-onset PE was higher than that of those with an uncomplicated pregnancy (47% (31/66) vs. 7.8% (5/64) respectively; p<0.01); 2) patients with late-onset PE and histological findings consistent with maternal underperfusion had a significantly lower median plasma concentration of PlGF, plasma PlGF/sVEGFR-1 ratio and plasma PlGF/sEng ratio than those with late-onset PE without placental underperfusion lesions (each p<0.05); 3) the most common pathological findings in the placenta of patient with PE were lesions consistent with villous changes (77%, 24/31); and 4) isolated vascular lesions in the placenta were found only in 2 cases (6.5%), and the rest had a combination of villous and vascular lesions.
Conclusions
Nearly half of the patients with late-onset PE have placental lesions consistent with maternal underperfusion. These lesions are associated with an imbalance in the maternal concentration of angiogenic/anti-angiogenic factors. We propose that there is a link between maternal underperfusion and an anti-angiogenic state characterized by the changes in the concentrations of angiogenic and anti-angiogenic factors in women with late onset PE.
doi:10.3109/14767058.2011.591461
PMCID: PMC3401571  PMID: 21867402
Placental growth factor (PlGF); soluble endoglin (sEng); soluble vascular endothelial growth factor receptor-1 (sVEGFR-1); soluble vascular endothelial growth factor receptor-2 (sVEGFR-2); ischemic placenta
15.  THE CHANGE IN CONCENTRATIONS OF ANGIOGENIC AND ANTI-ANGIOGENIC FACTORS IN MATERNAL PLASMA BETWEEN THE FIRST AND SECOND TRIMESTERS IN RISK ASSESSMENT FOR THE SUBSEQUENT DEVELOPMENT OF PREECLAMPSIA AND SGA 
Introduction
An imbalance between angiogenic and anti-angiogenic factors has been proposed as central to the pathophysiology of preeclampsia (PE). Indeed, patients with PE and those delivering small-for-gestational age (SGA) neonates have higher plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and the soluble form of endoglin (s-Eng), as well as lower plasma concentrations of vascual endothelial growth factor (VEGF) and placental growth factor (PlGF) than do patients with normal pregnancies. Of note, this imbalance has been observed before the clinical presentation of PE or the delivery of an SGA neonate. The objective of this study was to determine if changes in the profile of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters are associated with a high risk for the subsequent development of preeclampsia and/or delivery of an SGA neonate.
Methods
This longitudinal case-control study included 402 singleton pregnancies in the following groups: 1) normal pregnancies with appropiate for gestational age (AGA) neonates (n=201); 2) patients who delivered an SGA neonate (n=145); and 3) patients who developed PE (n=56). Maternal plasma samples were obtained at the time of each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. In this study, we included two samples per patient: 1) first sample obtained between 6 and 15 weeks of gestation (“first trimester” sample); and 2) second sample obtained between 20 and 25 weeks of gestation (“second trimester” sample). Plasma concentrations of s-Eng, sVEGFR-1 and PlGF were determined by specific and sensitive immunoassays. Changes in the maternal plasma concentrations of these angiogenesis-related factors were compared among normal patients and those destined to develop PE or deliver an SGA neonate while adjusting for maternal age, nulliparity and body mass index (BMI). General linear models and polytomous logistic regression models were used to relate the analyte concentrations, ratios, and product to the subsequent development of delivery of an SGA neonate.
Results
1) An increase in the maternal plasma concentration of s-Eng between the first and second trimesters conferred risk for the development of preterm PE and SGA (OR 14.9, 95% CI 4.9-45.0, and OR 2.9, 95% CI 1.5-5.6, respectively); 2) An increase in the maternal plasma concentration of sVEGFR-1 between the first and second trimester conferred risk for the development of preterm PE (OR 3.9, 95% CI 1.2-12.6); 3) A subnormal increase in maternal plasma PlGF concentration between the first and the second trimester was a risk factor for the subsequent development of preterm and term PE (OR 4.3, 95% CI 1.2-15.5, and OR 2.7, 95% CI 1.2-5.9, respectively); 4) In addition, the combination of the three analytes into a pro-angiogenic versus anti-angiogenic ratio [PlGF/(sEng x VEGFR-1)] conferred risk for the subsequent development of preterm preeclampsia (OR 3.7, 95% CI 1.1-12.1); 5) Importantly, patients with a high change in the s-Eng x sVEGFR-1 product had an OR of 10.38 (95% CI 3.18-33.84) for the development of preterm PE and 1.62 (95% CI 1.01-2.60) for the development of SGA.
Conclusion
Changes in the maternal plasma concentrations of s-Eng, sVEGFR-1, PlGF or their ratios between the first and second trimesters of pregnancy confer an increased risk to deliver a SGA neonate and/or develop PE.
doi:10.1080/14767050802034545
PMCID: PMC2846114  PMID: 18446652
SGA; longitudinal; PlGF; endoglin; sVEGFR-1
16.  Serum Concentrations of Soluble Flt-1 Are Decreased among Women with a Viable Fetus and No Symptoms of Miscarriage Destined for Pregnancy Loss 
PLoS ONE  2012;7(2):e32509.
Miscarriage is the most common complication of pregnancy. Pre-clinical miscarriage has an estimated incidence of 30%, whilst clinical miscarriage has an incidence of 12-15%. Two thirds of pregnancies lost to miscarriage are believed to be attributable to defective placentation, thus a number of studies have sought to identify markers of defective placentation that could be used as clinical biomarkers of miscarriage. Decreased soluble FMS-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin (sEng) in the maternal circulation during the first trimester have recently been proposed as potential markers of pregnancy loss. However, in these studies clinical samples were only obtained once women had presented with symptoms of miscarriage. In this study we prospectively screened serum samples collected from asymptomatic women with a viable fetus. We assessed maternal serum levels of sFlt1, PlGF and sEng across the first trimester of normal pregnancy and compared levels between women who continued to a live birth, to those who subsequently miscarried. Both sFlt1 and PlGF significantly (p≤0.05) increased across gestation in normal pregnancy with serum levels rising from 0.65±0.12 ng/ml at 6 weeks to 1.85±0.24 ng/ml at 12 weeks for sFlt1, and 57.2±19.2 pg/ml to 106±22.7 pg/ml for PlGF. sEng remained unchanged throughout the the first trimester. Importantly we detected a significant (35%, p≤0.05) decrease in sFlt1 levels between our control and miscarriage cohort, however there was significant overlap between cases and controls, suggesting serum sFlt1 is unlikely to be useful as a clinical biomarker in asymptomatic women. Nevertheless, our data suggests a dysregulation of angiogenic factors may be involved in the pathophysiology of miscarriage.
doi:10.1371/journal.pone.0032509
PMCID: PMC3289655  PMID: 22389705
17.  MATERNAL PLASMA CONCENTRATIONS OF ANGIOGENIC/ANTI-ANGIOGENIC FACTORS ARE OF PROGNOSTIC VALUE IN PATIENTS PRESENTING TO THE OBSTETRICAL TRIAGE AREA WITH THE SUSPICION OF PREECLAMPSIA 
Objective
To determine if maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and -2 could identify patients at risk for developing preeclampsia (PE) requiring preterm delivery.
Study design
Patients presenting with the diagnosis ‘rule out PE’ to the obstetrical triage area of our hospital at <37 weeks of gestation (n=87) were included in this study. Delivery outcomes were used to classify patients into 4 groups: I) patients without PE or those with gestational hypertension (GHTN) or chronic hypertension (CHTN) who subsequently developed PE at term (n=19); II): mild PE who delivered at term (n=15); III): mild disease (mild PE, GHTN, CHTN) who subsequently developed severe PE requiring preterm delivery (n=26); and IV): diagnosis of severe PE (n=27). Plasma concentrations of PlGF, sEng, sVEGFR-1 and -2 were determined at the time of presentation by ELISA. Reference ranges for analytes were constructed by quantile regression in our laboratory (n=180; 1,046 samples). Comparisons among groups were performed using multiples of the median (MoM) and parametric statistics after log transformation. Receiver operating characteristic curves, logistic regression and survival analysis were employed for analysis.
Results
The mean MoM plasma concentration of PlGF/sVEGFR-1, PlGF/sEng, PlGF, sVEGFR-1 and -2, and sEng in Group III was significantly different from Group II (all p<0.05). A plasma concentration of PlGF/sVEGFR-1 ≤ 0.05 MoM or PlGF/sEng ≤ 0.07 MoM had the highest likelihood ratio of a positive test (8.3, 95% CI 2.8–25 and 8.6, 95% CI 2.9–25, respectively), while that of PlGF ≤0.396 MoM had the lowest likelihood ratio of a negative test (0.08, 95% CI 0.03–0.25). The association between low plasma concentrations of PlGF/sVEGFR-1 (≤0.05 MoM) as well as that of PlGF/sEng (≤ 0.07 MoM) and the development of severe PE remained significant after adjusting for gestational age at presentation, average systolic and diastolic blood pressure, and a history of chronic hypertension [adjusted odds ratio (OR) = 27 (95% CI 6.4–109) and adjusted OR 30 (95% CI 6.9–126), respectively]. Among patients who presented <34 weeks gestation (n=59), a plasma concentration of PlGF/sVEGFR-1 <0.033 MoM identified patients who delivered within 2 weeks because of PE with a sensitivity of 93% (25/27) and a specificity of 78% (25/32). This cut-off was associated with a shorter interval-to-delivery due to PE [hazard ratio = 6 (95% CI 2.5–14.6)].
Conclusions
Plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in the obstetrical triage area. These observations support the value of these biomarkers in the clinical setting for the identification of the patient at risk for disease progression requiring preterm delivery.
doi:10.3109/14767058.2011.589932
PMCID: PMC3384532  PMID: 21827221
placental growth factor (PlGF); soluble endoglin (sEng); soluble vascular endothelial growth factor receptor-1 (sVEGFR-1); soluble vascular endothelial growth factor receptor-2 (sVEGFR-2); preeclampsia; IUGR; preterm labor; automated assay; angiogenesis; sflt-1
18.  Soluble Endoglin, Transforming Growth Factor-Beta 1 and Soluble Tumor Necrosis Factor Alpha Receptors in Different Clinical Manifestations of Preeclampsia 
PLoS ONE  2014;9(5):e97632.
Background
Despite intensive research, the etiopathogenesis of preeclampsia (PE) remains uncertain. Inflammatory and angiogenic factors are thought to play considerable roles in this disease. The objective of this study was to investigate the association between soluble endoglin (sEng), transforming growth factor beta-1 (TGF-β1) and tumor necrosis factor alpha soluble receptors (sTNF-Rs) and the clinical manifestations of PE.
Methods
Plasma levels of sEng, TGF-β1 and sTNF-Rs were determined by ELISA in 23 non-pregnant, 21 normotensive pregnant and 43 PE women. PE women were stratified into subgroups according to the severity [mild (n = 12) and severe (n = 31)] and onset-time of the disease [early (n = 19) and late (n = 24)].
Results
Pregnancy was associated with higher levels of sEng, sTNF-R1 and sTNF-R2 than the non-pregnant state. Moreover, PE women had higher levels of sEng and sTNF-R1 than normotensive pregnant women. No difference was found in TGF-β1 levels, comparing the three study groups. Late PE had higher levels of sTNF-R1 and sTNF-R2 than early PE. No significant differences were found in sEng and TGF-β1 comparing early and late PE. sEng levels were higher in severe PE than in mild PE and no difference was found for TGF-β1, sTNF-R1 and sTNF-R2 levels. There was a positive correlation among sEng, TNF-R1 and sTNF-2 levels. Logistic regression analysis revealed that primiparity and sEng levels are independently associated with the development of PE. Furthermore, sEng levels are independently associated with the disease severity.
Conclusions
These results suggest that pregnancy is a condition associated with higher levels of anti-angiogenic and pro-inflammatory factors than the non-pregnant state and that PE is associated with an imbalance of these factors in the maternal circulation.
doi:10.1371/journal.pone.0097632
PMCID: PMC4031102  PMID: 24851923
19.  Maternal Angiogenic Profile in Pregnancies that Remain Normotensive 
Objective
We sought to determine if maternal characteristics are associated with angiogenic profile in the first and second trimester of normotensive pregnancies.
Study Design
Circulating levels of maternal placental like growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt1), and soluble endoglin (sEng) were measured in serum samples collected during the first (median 11.3 weeks) and second trimester (median 17.1 weeks) of 182 normotensive pregnancies. Diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MAP) were measured at the same visits when samples were collected to measure angiogenic factors. Linear regression analysis was used to examine associations of the angiogenic measures with maternal characteristics. The association between blood pressure measures and concentrations of angiogenic factors was evaluated using Spearman correlation and linear regression analysis.
Results
In adjusted analyses, nulliparous women had higher sFlt1 concentrations in both first (P=0.06) and second (P=0.001) trimester. Higher BMI was associated with greater sFlt1 concentrations in both the first (P=0.004) and second trimester (P=0.008), but significantly lower sEng concentrations in both trimesters (P=0.002 for first trimester and P=0.0009 for second). Nulliparity and higher BMI also were associated with higher sFlt1/PLGF anti-angiogenic ratios in both first (p=0.05 and p=0.007, respectively) and second trimesters (p=0.003 and p=0.02, respectively). First trimester sFlt1 levels were weakly correlated with first trimester SBP (rs=0.18, p=0.03) and MAP (rs=0.16, p=0.04). Second trimester sEng levels were inversely associated with second trimester MAP (rs= −0.17, p=0.05). Including blood pressure measures in the linear regression models did not change the reported associations of angiogenic factors with maternal characteristics.
Conclusions
These results demonstrate that even early in normotensive pregnancies maternal characteristics are associated with variations in angiogenic profile across this population.
doi:10.1016/j.ejogrb.2011.05.001
PMCID: PMC3302581  PMID: 21641103
Pregnancy; angiogenic factors; sFlt1; PlGF; soluble endoglin; maternal
20.  Angiogenic Factors and Renal Disease in Pregnancy 
Background. Preeclampsia is difficult to diagnose in patients with underlying renal disease and proteinuria. Prior studies show that there is an angiogenic factor imbalance with elevated levels of antiangiogenic proteins soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) and reduced levels of the proangiogenic protein, placental growth factor (PlGF) in women with preeclampsia. These angiogenic biomarkers may be useful in distinguishing preeclampsia from other conditions of pregnancy, which may present with overlapping clinical characteristics. Cases. Case 1: A multiparous woman at 18 weeks gestation with nephrotic syndrome presented with hypertensive emergency and worsening renal insufficiency. She underwent induction of labor for severe preeclampsia. Her sFlt1 and sEng levels were at the 97 percentile while her PlGF level was undetectable (less than the 1st percentile). Case 2: A nulliparous woman with lupus nephritis at 22 weeks gestation presented with fetal demise and heart failure. Three weeks previously, the patient had developed thrombocytopenia and hypertensive urgency. She underwent dilation and evacuation. Her angiogenic profile was consistent with severe preeclampsia. Conclusion. Angiogenic factors may provide evidence to support a diagnosis of preeclampsia in patients with preexisting renal disease and proteinuria, conditions in which the classical definition of hypertension and proteinuria cannot be used.
doi:10.1155/2011/281391
PMCID: PMC3335608  PMID: 22567501
21.  CHBPR-HYPERTENSION PRODUCED BY PLACENTAL ISCHEMIA IN PREGNANT RATS IS ASSOCIATED WITH INCREASED SOLUBLE ENDOGLIN EXPRESSION 
Hypertension  2008;53(2):399-403.
Recent clinical studies indicate an excess of angiostatic factors such as soluble endoglin (sEng) is related to the occurrence of preeclampsia. Although recent clinical studies report that sEng is increased in preeclamptic women, the mechanisms underlying its over-expression remain unclear. Evidence suggests that hypoxia and induction of heme oxygenase-1 (HO-1) have opposing effects on sEng expression, the former stimulatory and the latter inhibitory. Hence, we hypothesized that placental ischemia due to reduced uterine perfusion pressure (RUPP) in the pregnant rat would increase sEng expression, and decrease HO-1. Mean arterial pressure (MAP) was obtained via arterial catheter and serum and placental proteins were measured by western blot. MAP was increased (132±3 vs. 102±2 mm Hg; P<0.001) and fetal (2.35±0.05 vs. 1.76±0.08 g; P<0.001) and placental weight were decreased (0.47±0.04 vs. 0.58±0.03 g; P<0.01) in the RUPP compared to normal pregnant (NP) controls. Serum sEng (0.10±0.02 vs. 0.05±0.01 arbitrary pixel units (apu); P<0.05) and placental Eng (4.7±2.3 vs. 1.45±0.42 apu; P<0.05) were increased along with placental HIF1-α (1.42±0.25 vs. 0.68 ± 0.09 apu; P < 0.05) expression in the RUPP vs. the NP dams. Placental HO-1 (1.4±0.3 vs. 2.5±0.1 apu; P<0.05) expression decreased in the RUPP compared to NP dams. The present findings support our hypothesis that placental ischemia due to RUPP increases the expression of sEng and shifts the balance of angiogenic factors in the maternal circulation towards an angiostatic state. The present study provides further evidence that placental ischemia is a strong in vivo stimulus of angiostatic factors during pregnancy.
doi:10.1161/HYPERTENSIONAHA.108.123513
PMCID: PMC2692089  PMID: 19075097
preeclampsia; gestation; endoglin; blood pressure
22.  Circulating anti-angiogenic factors during hypertensive pregnancy and increased risk of respiratory distress syndrome in preterm neonates 
Objective: To test the hypothesis that high circulating concen-trations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS). Study Design: This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hyperten-sion and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endo-glin (sEng) in maternal serum were measured at 21–32 weeks of gestation. Results: Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5% vs. 20.9%, p =0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% CI 1.08–4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during midpregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL vs. 7,000 pg/mL, p =0.01). Conclusions: Preterm preeclampsia and gestational hypertension, charac-terized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during midpregnancy were substantially higher in women whose infants developed RDS.
doi:10.3109/14767058.2011.640368
PMCID: PMC3414194  PMID: 22097923
Anti-angiogenic; soluble fms-like tyrosine kinase 1; sVEGF R1; sFlt1; placental growth factor; PlGF; soluble endoglin; sEng; respiratory distress syndrome; RDS; neonate; preterm; preeclampsia; gestational hypertension
23.  Serum and plasma determination of angiogenic and anti-angiogenic factors yield different results: the need for standardization in clinical practice 
Objective
The importance of an anti-angiogenic state as a mechanism of disease in preeclampsia is now recognized. Assays for the determination of concentrations of soluble vascular endothelial growth factor receptor (sVEGFR)-1, sVEGFR-2, placental growth factor (PlGF) and soluble endoglin (sEng) have been developed for research and clinical laboratories. A key question is whether these factors should be measured in plasma or serum. The purpose of this study was to determine if there are differences in the concentrations of these analytes between plasma and serum in normal pregnancy and in preeclampsia.
Methods
Samples of maternal blood were obtained by venipuncture and collected in EDTA (lavender top) and serum collection tubes (red top). A standard laboratory procedure was implemented for the centrifugation, aliquoting and storage of samples. Plasma and serum from 70 women with normal pregnancies and 34 patients with preeclampsia, were assayed for sVEGFR-1, sVEGFR-2, PlGF and sEng by ELISA. Non-parametric paired tests were used for analyses.
Results
A significant difference between plasma and serum concentration was observed for sVEGFR-1 and sVEGFR-2 in normal pregnancy, and for sVEGFR-1, sVEGFR-2, PlGF and sEng in women with preeclampsia.
Conclusion
The concentrations of sVEGFR-1, sVEGFR-2, PlGF and sEng when measured in maternal plasma and in serum are different. Therefore, the matrix used for the assay (serum versus plasma) needs to be considered when selecting thresholds for predictive studies and interpreting the growing body of literature on this subject.
doi:10.3109/14767050903366119
PMCID: PMC3426311  PMID: 20158394
preeclampsia; anti-angiogenic state; sFlt-1; sVEGFR-1; sVEGFR-2; PlGF; placental growth factor; sEng; soluble Endoglin; vascular endothelial growth factor; pregnancy
24.  Circulating angiogenic modulatory factors predict survival and functional class in pulmonary arterial hypertension 
Pulmonary Circulation  2013;3(2):369-380.
The diagnosis of pulmonary arterial hypertension (PAH) is frequently delayed. We hypothesized that circulating angiogenic modulatory protein levels might correspond with vascular remodeling activity and serve as sensitive biomarkers of PAH. Levels of soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR1), N-terminal brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and other biomarkers were measured in peripheral blood from 97 PAH patients, 16 first-degree relatives of idiopathic or heritable pulmonary arterial hypertension (HPAH) patients, and 56 controls, and correlated with disease, functional class, hemodynamic parameters, exercise capacity, and transplant-free survival. Endoglin expression was analyzed in lung tissues of six individuals with idiopathic or HPAH and four individuals without PAH. Levels of sEng, sVEGFR1, CRP, and NT-proBNP were elevated in Group I PAH of diverse etiologies, with sEng performing better than NT-proBNP in detecting PAH (receiver operator characteristic-area-under-the curve [ROC-AUC] of 0.82 ± 0.03 vs. 0.71 ± 0.05, P = 0.016). While sEng, sVEGFR1, and NT-proBNP correlated with New York Heart Association (NYHA) class, sEng levels were more sensitive than NT-proBNP in detecting NYHA Class I-II disease (ROC-AUC of 0.88 ± 0.05 vs. 0.67 ± 0.08, P = 0.028). sEng, sVEGFR1, CRP, and NT-proBNP predicted transplant-free survival by univariate Cox regression. After adjusting for NT-proBNP levels, each of the other three markers predicted transplant-free survival. In multivariate analysis, sEng and CRP were independent predictors of survival. Endoglin expression was markedly enhanced in the microvascular endothelium and endovascular lesions of PAH versus control lung tissues. Circulating angiogenic proteins sEng and sVEGFR1 are sensitive markers of prognosis and function in Group I PAH, including mildly symptomatic disease, and may provide unique noninvasive data reflecting underlying remodeling activity.
doi:10.4103/2045-8932.110445
PMCID: PMC3757832  PMID: 24015338
angiogenesis; biomarkers; endoglin; pulmonary arterial hypertension; VEGF receptor-1
25.  Endoglin in Amniotic Fluid as a Risk Factor for the Subsequent Development of Bronchopulmonary Dysplasia 
Objective
Cross-talk between inflammation and angiogenesis pathways has been recently reported. The objective of this study was to: 1) examine whether amniotic fluid (AF) concentrations of soluble endoglin (sEng), a protein with anti-angiogenic properties, changes during pregnancy, parturition or intraamniotic infection and/or inflammation (IAI); 2) determine whether an elevation of sEng in the AF of patients with preterm labor (PTL) and preterm prelabor rupture of membranes (PROM) is associated with adverse neonatal outcomes; and 3) investigate potential sources of sEng in AF.
Study Design
A cross-sectional study was conducted to include patients in the following groups: 1) midtrimester (n=20); 2) PTL with term delivery (n=95); 3) PTL leading to preterm delivery with (n=40) and without IAI (n=46); 4) preterm PROM with (n=37) and without IAI (n=37); 5) term in labor (n=48) and not in labor (n=44). AF concentrations of sEng were determined by ELISA. Chorioamniotic membranes, umbilical cord blood and AF macrophages were examined for the expression of endoglin.
Results
1) Patients with IAI had a higher median AF concentration of sEng than those without IAI (p=0.02 for PTL; and 0.06 for preterm PROM); 2) AF concentrations of sEng in the 3rd and 4th quartiles were associated with IAI (OR 2.5 and 7.9 respectively); 3) an AF sEng concentration ≥779.5 pg/ml was associated with bronchopulmonary dysplasia (BPD) (OR 7.9); 4) endoglin was co-localized with CD14+ macrophages in AF pellets of patients with IAI by immunofluorescence and flow cytometry; and 5) the concentration of sEng in the supernatant was significantly increased after treatment of macrophages with endotoxin or TNF-α.
Conclusions
sEng participates in the host response against IAI. Activated macrophages may be a source of sEng concentrations in the AF of patients with IAI. An increase of sEng in the AF is associated with BPD and adverse neonatal outcomes.
doi:10.1111/aji.12046
PMCID: PMC4151572  PMID: 23279628
preterm labor; preterm prelabor rupture of membranes; angiogenesis; adverse neonatal outcomes; intraamniotic infection; intraamniotic inflammation

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