PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (696021)

Clipboard (0)
None

Related Articles

1.  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
2.  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
3.  Blood pressure augmentation and maternal circulating concentrations of angiogenic factors at delivery in preeclamptic and uncomplicated pregnancies 
Objective
The objective of the study was to determine whether blood pressure increases are associated with maternal angiogenic factors in uncomplicated and preeclamptic pregnancies.
Study Design
Associations of blood pressure increases from mid- to late pregnancy with maternal serum concentrations of soluble fms-like tyrosine kinase receptor (sFlt1), soluble endoglin (sEng), and placental growth factor (PlGF) at delivery were analyzed in 43 uncomplicated and 44 preeclamptic pregnancies.
Results
In uncomplicated pregnancies, increases in diastolic and mean arterial pressure were inversely associated with PlGF at delivery and positively associated with sEng and sFlt1/PlGF ratio. There were no significant associations between blood pressure increases and angiogenic factor concentrations in preeclampsia.
Conclusion
These data suggest that angiogenic factors are involved in blood pressure modulation in normotensive pregnancy and are consistent with the hypothesis that angiogenic balance plays a role in maternal breast cancer risk reduction associated with mid- to late blood pressure increases in uncomplicated pregnancies.
doi:10.1016/j.ajog.2008.06.030
PMCID: PMC2646178  PMID: 18722574
angiogenic factors; blood pressure; breast cancer; preeclampsia; pregnancy
4.  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
5.  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
6.  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
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 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
8.  Circulating Angiogenic and Anti-Angiogenic Factors in Pregnant Women with Eclampsia 
Objective
To determine if eclampsia has a different circulating profile of angiogenic [placental growth factor (PlGF)] and anti-angiogenic factors [soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and soluble endoglin (sEng)] than severe preeclampsia.
Study Design
This cross-sectional study included women in the following groups: 1) normal pregnancy (n=40); 2) severe preeclampsia (n=40); and 3) eclampsia (n=20). Maternal serum PlGF, sVEGFR-1, and sEng concentrations were determined using ELISA.
Results
1) The median concentration of sVEGFR-1 and sEng was higher and of PlGF lower in severe preeclampsia or eclampsia than in normal pregnancy (p<0.001 for all); 2) the median concentrations of these 3 analytes did not differ significantly between the severe preeclampsia and eclampsia groups.
Conclusions
Eclampsia is associated with higher maternal circulating concentrations of sVEGFR-1 and sEng and lower concentrations of PlGF than normal pregnancy, but with similar concentrations to severe preeclampsia. These findings suggest that eclampsia shares a common pathogenic pathway as severe preeclampsia.
doi:10.1016/j.ajog.2010.08.049
PMCID: PMC3057127  PMID: 21062661
placental growth factor; PlGF; preeclampsia; pregnancy; sEng; sFlt-1; soluble endoglin; soluble vascular endothelial growth factor receptor-1; sVEGFR-1
9.  Second trimester anti-angiogenic proteins and preeclampsia 
Pregnancy hypertension  2012;2(2):158-163.
Objective
To measure the relationships between soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng) and preeclampsia.
Study design
We utilized a nested case-control study comprised of 211 preeclamptic women and 213 normotensive women with primiparous singleton pregnancies enrolled from ≥13 and <27 gestational weeks among the Danish National Birth Cohort of 100,000 women. Relationships between sFlt1, sEng and preeclampsia were estimated using smoothing splines in generalized linear models, adjusting for maternal age, body mass index, pre-existing hypertension, smoking, and gestational age.
Main outcome measures
Preeclampsia was confirmed by an International Classification of Diseases (ICD) discharge diagnosis of 637.03, 637.04 637.09, 637.19 (ICD-8) or DO14 to DO15 (ICD-10) in the National Hospital Discharge Registry. In this sample, few cases delivered small for gestational age infants (8.1%) and the mean gestational age at delivery was term (38.2 ± 2.3 weeks).
Results
Doublings in the expressions of sFlt1 and sEng were associated with 39% (95% CI = 3%, 86%) and 74% (95% CI = 1%, 198%) increased risks of preeclampsia respectively.
Conclusions
We conclude that second trimester high sFlt1 and sEng levels were possibly associated with an increased risk of preeclampsia after adjustment for maternal factors traditionally associated with the syndrome.
doi:10.1016/j.preghy.2012.01.005
PMCID: PMC3375839  PMID: 22712058
10.  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
11.  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
12.  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
13.  Mid-pregnancy levels of angiogenic markers in relation to maternal characteristics 
Objective
To describe relations among maternal demographic and lifestyle characteristics and mid-pregnancy levels of angiogenic markers (soluble Fms-like tyrosine kinase-1 (sFlt-1); placental growth factor (PlGF); soluble endoglin (sEng)).
Study Design
In a large pregnancy cohort, linear models were used to evaluate relations among maternal characteristics and mid-pregnancy angiogenic markers with and without covariate adjustment. Associations were examined in a sub-cohort including term and preterm deliveries (N = 1302) and among “normal” term pregnancies (N = 668).
Results
Concentrations of all factors declined with increasing maternal BMI. Multiparous women had lower sFlt-1 levels than primiparas. Higher PlGF and slightly lower sEng were observed among women who smoked at enrollment, but not among those who quit before enrollment. African-American women had higher levels of all markers.
Conclusions
Understanding relations among maternal characteristics and levels of angiogenic factors may improve studies utilizing these markers to examine etiologies and/or to predict adverse pregnancy outcome.
doi:10.1016/j.ajog.2010.10.001
PMCID: PMC3079927  PMID: 21145529
preeclampsia; angiogenic factors; soluble endoglin; placental growth factor; soluble Fms-like tyrosine kinase-1
14.  Maternal Circulating Levels of Activin A, Inhibin A, sFlt-1 and Endoglin at Parturition in Normal Pregnancy and Pre-Eclampsia 
PLoS ONE  2009;4(2):e4453.
Background
Maternal circulating levels of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1), endoglin (sEng) and placental proteins like activin A and inhibin A are increased before the onset of pre-eclampsia. There is evidence for oxidative stress in pre eclampsia. Recently it was shown that placental oxygen concentration is related to sFlt-1 and inhibin A. In addition it is reported that oxidative stress markers are increased in placental tissue delivered after labour. Therefore, the objective of this study is to investigate if these proteins are altered in maternal circulation of labouring pre-eclampsia and normal pregnancies.
Methodology
To assess the effects of labour, samples were taken from 10 normal pregnant (NP) and 10 pre-eclamptic (PE) women pre-labour, full dilation, placental delivery and 24 h. To assess the effects of placental delivery, plasma samples were taken from 10NP and 10PE women undergoing elective Caesarean section, pre-delivery, placental delivery and 10 min, 60 min and 24 h post delivery. SFlt-1 and sEng and activin A and inhibin A were measured using commercial and in house ELISA's respectively.
Results
The levels of sFlt-1 and sEng were significantly higher in PE compared to NP women in both groups. In labour, sFlt-1 levels increased significantly at full dilatation in PE women, before declining by 24 hr. However there was no significant rise in sEng levels in labour. Activin A and inhibin A levels declined rapidly with placental delivery in NP and PE pregnancies. There was a significant rise in activin A levels during labour in PE compared to pre labour, but inhibin levels did not increase.
Conclusion
Labour in pre-eclamptic women increases the levels of sFlt-1 and activin A. This pilot data suggests that increase in the maternal levels of these factors in labour could predict and/or contribute to the maternal syndrome postpartum.
doi:10.1371/journal.pone.0004453
PMCID: PMC2675175  PMID: 19412349
15.  Angiotensin II and angiotensin-(1-7) decrease sFlt1 release in normal but not preeclamptic chorionic villi: an in vitro study 
Background
During preeclampsia, placental angiogenesis is impaired. Factors released from the placenta including vascular endothelial growth factor (VEGF), placental growth factor (PLGF), soluble VEGF receptor 1 (sFlt1), and soluble endoglin (sEng) are regulatory molecules of placental development and function. While the renin angiotensin system has been shown to regulate angiogenic factors in other research fields, these mechanisms have not been extensively studied during pregnancy.
Methods
We evaluated the effects of angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)] on the release of VEGF, PLGF, sFlt1, and sEng from placental chorionic villi (CV). CV were collected from nulliparous third-trimester normotensive and preeclamptic subjects. CV were incubated for 0, 2, 4, and 16 hours with or without Ang II (1 nM and 1 microM) or Ang-(1-7) (1 nM and 1 microM). The release of VEGF, PLGF, sFlt1, sEng, lactate dehydrogenase (LDH), and human placenta lactogen (HPL) was measured by ELISA.
Results
The release of sFlt1, PLGF, sEng from normal and preeclamptic CV increased over time. Release of sFlt1 and sEng was significantly higher from preeclamptic CV. VEGF was below the detectable level of the assay in normal and preeclamptic CV. After 2 hours, sFlt1 release from normal CV was significantly inhibited with Ang II (1 nM and 1 microM) and Ang-(1-7) (1 nM and 1 microM). There was a time-dependent increase in HPL indicating that the CV were functioning normally.
Conclusions
Our study demonstrates a critical inhibitory role of angiotensin peptides on sFlt1 in normal pregnancy. Loss of this regulation in preeclampsia may allow sFlt1 to increase resulting in anti-angiogenesis and end organ damage in the mother.
doi:10.1186/1477-7827-8-135
PMCID: PMC2989977  PMID: 21050477
16.  The elevation in circulating anti-angiogenic factors is independent of markers of neutrophil activation in preeclampsia 
Angiogenesis  2012;15(3):333-340.
Background
Severe preeclampsia is associated with increased neutrophil activation and elevated serum soluble endoglin (sEng) and soluble Flt-1 (sFlt-1) in the maternal circulation. To dissect the contribution of systemic inflammation and anti-angiogenic factors in preeclampsia, we investigated the relationships between the circulating markers of neutrophil activation and anti-angiogenic factors in severe preeclampsia or systemic inflammatory state during pregnancy.
Methods and results
Serum sEng, sFlt-1, placenta growth factor, interleukin-6 (IL-6), calprotectin, and plasma α-defensins concentrations were measured by ELISA in 88 women of similar gestational age stratified as: severe preeclampsia (sPE, n = 45), maternal systemic inflammatory response (SIR, n = 16) secondary to chorioamnionitis, pyelonephritis or appendicitis; and normotensive controls (CRL, n = 27). Neutrophil activation occurred in sPE and SIR, as α-defensins and calprotectin concentrations were two-fold higher in both groups compared to CRL (P < 0.05 for each). IL-6 concentrations were highest in SIR (P < 0.001), but were higher in sPE than in CRL (P < 0.01). sFlt-1 (P < 0.001) and sEng (P < 0.001) were ≈20-fold higher in sPE compared to CRL, but were not elevated in SIR. In women with sPE, anti-angiogenic factors were not correlated with markers of neutrophil activation (α-defensins, calprotectin) or inflammation (IL-6).
Conclusions
Increased systemic inflammation in sPE and SIR does not correlate with increased anti-angiogenic factors, which were specifically elevated in sPE indicating that excessive systemic inflammation is unlikely to be the main contributor to severe preeclampsia.
doi:10.1007/s10456-012-9261-5
PMCID: PMC3409369  PMID: 22398973
Soluble endoglin; Soluble Flt-1; Placenta growth factor; Preeclampsia; Neutrophil; Inflammation
17.  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
18.  Relationships among maternal nutrient intake and placental biomarkers during the 1st trimester in low-income women 
Purpose
Pre-eclampsia is a multi-system disorder caused by inadequate placentation in early pregnancy; however, little is known about the influence of nutrient intake on placental development during the crucial 1st trimester. The objective of this study was to examine the relationships between nutrient intake and the raw values and ratios of angiogenic [placental growth factor (PlGF)] and antiangiogenic [soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng)] placental biomarkers in the 1st trimester.
Methods
A cross-sectional study of low-income, pregnant women (n = 118). Average nutrient intake was calculated from three 24-h dietary recalls. Biomarker values were adjusted for gestational age and nutrients were adjusted for energy.
Results
The angiogenic to antiangiogenic ratio [PlGF/(sFlt-1 × sEng)] was positively related to intake of vitamin D (r = 0.24), vitamin B2 (r = 0.25), B12 (r = 0.20), dietary folate equivalents (r = 0.19), iron (r = 0.19), and zinc (r = 0.19) and negatively related to transfats (r = −0.24). Principal component analysis revealed that a vitamin/mineral factor [t (112) = 2.58, p = 0.011] and transfats factor [t (112) = −2.03, p = 0.045] were significant predictors of the PlGF/(sFlt-1 × sEng) ratio. The vitamin and mineral factor was a significant predictor of sFlt-1 [t (122) = 2.29, p = 0.024].
Conclusions
Expression of placental biomarkers in the early weeks of pregnancy may be influenced by intake of nutrients. Understanding the influence of maternal nutrient intake and placental development in the 1st trimester may provide the opportunity to avert the development or blunt the severity of preeclampsia.
doi:10.1007/s00404-011-2213-2
PMCID: PMC3322547  PMID: 22234787
Preeclampsia; Vitamin D; Transfats; Pregnancy; Low income; Placental growth factor; Soluble fms-like tyrosine kinase-1; Soluble endoglin
19.  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
20.  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
21.  The Effect of Maternal Thrombophilia on Placental Abruption: Histologic Correlates 
Objective
To determine if the histology of placental abruption differs by maternal thrombophilia status.
Study design
This was a multicenter, case-control study of women with abruption and delivering at ≥20 weeks’ gestation, collected as part of the ongoing New Jersey-Placental Abruption Study. Women were identified by clinical criteria of abruption. Maternal blood was collected postpartum and tested for anticardiolipin antibodies, and mutations in the Factor V Leiden and prothrombin genes. Cases were comprised of women with an abruption and a positive thrombophilia screen. Controls were comprised of women with an abruption and a negative thrombophilia screen. All placental histology was systematically reviewed by two perinatal pathologists, blinded to the abruption status.
Results
A total of 135 women with placental abruption were identified, of which 63.0% (n=85) had at least one diagnosed maternal thrombophilia. There were increases in the rates of meconium-stained membranes (7.9% versus 2.1%, P=0.015) and decidual necrosis (4.5% versus 2.1%, P=0.023) when a maternal thrombophilia was diagnosed. Although there was no difference in the overall presence of infarcts between the 2 groups (27.0% versus 38.3%, P=0.064), the presence of an old infarct was more common among women with a positive thrombophilia screen (83.3% versus 44.4%, P=0.003).
Conclusion
Placental abruption with a positive maternal thrombophilia screen is associated with higher rates of old placental infarcts and decidual necrosis compared with abruption when thrombophilia is not diagnosed. These lesions suggest a chronic etiology of placental abruption in the presence of a maternal thrombophilia.
doi:10.1080/14767050802551795
PMCID: PMC3192526  PMID: 19330709
22.  Usefulness of Soluble Endoglin as a Non-invasive Measure of Left Ventricular Filling Pressure in Heart Failure 
The American Journal of Cardiology  2010;106(12):1770-1776.
Progressive left ventricular (LV) dysfunction induces expression of the cytokine transforming growth factor-beta (TGFb1). Endoglin (CD105) is a TGFb1 co-receptor that is released into the circulation as soluble endoglin (sEng). The objective of this study was to assess serum levels of sEng in heart failure and to identify the predictive value of sEng for detecting elevated left ventricular end-diastolic pressures (LVEDP). We measured sEng levels in 82 consecutive patients with suspected LV dysfunction referred for determination of left heart filling pressures by cardiac catheterization. Among these subjects sEng levels correlated with LVEDP (R=0.689; p<0.0001) irrespective of LV ejection fraction (LVEF). Using a receiving operative characteristic (ROC) curve, sEng levels predicted an LVEDP≥16mmHg with an area-under-the-curve (AUC) of 0.85, exceeding measured AUCs for both atrial- and brain-natriuretic peptide, currently used biomarkers for heart failure diagnosis (ANP:0.68; BNP:0.65, p<0.01 vs sEng respectively). In 10 subjects receiving medical therapy for heart failure guided by invasive hemodynamic monitoring, decreased pulmonary capillary wedge pressure was associated with a reduced sEng level (R=0.75, p=0.008). Finally, compared to 25 healthy controls, sEng levels were elevated in subjects with suspected LV dysfunction (3589±588 vs 4257±966 pg/mL, respectively, p<0.005) and correlated directly with New York Heart Association class (NYHA; R=0.501, p<0.001). In conclusion, circulating levels of sEng are elevated in patients with increased LVEDP and NYHA class, irrespective of LVEF. Soluble endoglin levels also decrease in association with reduced cardiac filling pressure after diuresis. These findings identify circulating sEng as a sensitive measure of elevated left heart filling pressure.
doi:10.1016/j.amjcard.2010.08.018
PMCID: PMC3353730  PMID: 21126621
heart failure; cardiac filling pressure; soluble receptors
23.  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
24.  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
25.  Variation in endoglin pathway genes is associated with preeclampsia: a case–control candidate gene association study 
Background
Preeclampsia is a hypertensive, multi-system pregnancy disorder whose pathophysiology remains unclear. Elevations in circulating soluble endoglin (sENG) and placental/blood ENG mRNA expression antedate the clinical onset of preeclampsia. This study investigated if endoglin (ENG) pathway genetic variation was also associated with the development of preeclampsia.
Methods
We used a case–control candidate gene association design. Data from 355 white (181 preeclampsia cases/174 controls) and 60 black (30 preeclampsia cases/30 controls) women matched on ancestry, age, and parity were analyzed. Tagging single nucleotide polymorphisms (tSNPs) and potentially functional SNPs in ENG, TGFβ1, TGFβR1, ALK1, and TGFβR2 were genotyped with iPLEX® and TaqMan®. Chi-square or Fisher’s exact tests were used to conduct allele/genotype/haplotype tests in white/black subgroups separately. Odds ratios were computed with binary logistic regression for tSNPs with significant genotype tests.
Results
Of the 49 SNPs evaluated, variation in two ENG tSNPs (rs11792480, rs10121110) and one TGFβR2 tSNP (rs6550005) was associated with preeclampsia in white women (P <0.05, each). In black women, variation in two TGFβ1 tSNPs (rs4803455, rs4803457), one TGFβR1 tSNP (rs10739778), and three TGFβR2 tSNPs (rs6550005, rs1346907, rs877572) was associated with preeclampsia (P <0.05, each). Further evaluation of ENG tSNP rs10121110 revealed that white women inheriting the AA genotype were 2.29 times more likely to develop preeclampsia compared to the GG genotype (P = 0.008, [99% CI: 1.02 to 5.13]). For black women, similar evaluation of TGFβ1 tSNP rs4803457 revealed women inheriting the CT genotype were 7.44 times more likely to develop preeclampsia than those with the CC genotype (P = 0.005, [99% CI: 1.19 to 46.41]).
Conclusions
ENG pathway genetic variation is associated with preeclampsia. Different ENG pathway genes may be involved in preeclampsia development among white and black women. Additional studies are needed to validate these findings and to determine if genetic variation in ENG pathway genes impacts ENG and sENG levels in preeclampsia.
doi:10.1186/1471-2393-13-82
PMCID: PMC3651360  PMID: 23548068
Endoglin; Genetic association study; Preeclampsia; SNP

Results 1-25 (696021)