Significant decrease in maternal serum concentrations of angiopoietin-1 and -2 after delivery.

OBJECTIVE: To characterize the physiological distribution of angiopoietins (Ang)-1 and Ang-2 and soluble endothelial cell-specific tyrosine kinase receptor-2 (Tie-2) at term and following delivery. DESIGN: A prospective, descriptive study. SETTING: Helsinki University Central Hospital. POPULATION: Twenty healthy term pregnant women undergoing elective cesarean delivery and their newborns. METHODS: The concentrations were analysed by enzyme-linked immunosorbent assay in maternal antepartum and the first postpartum day sera, umbilical serum, amniotic fluid and maternal and newborn urine. MAIN OUTCOME MEASURES: Concentrations of Ang-1, Ang-1 and Tie-2. Results. Concentrations of maternal serum Ang-1 and Ang-2 decreased after delivery {[median (range)]: Ang-1, from 33 (25-51) to 30 (18-49) ng/mL, p= 0.017; and Ang-2, from 5.4 (1.8-18) to 1.4 (0.7-4.6) ng/mL, p < 0.0001}, whereas Tie-2 concentrations remained stable [23 (13-41) vs. 25 (14-29) ng/mL, p= 0.107]. Compared with maternal antepartum serum, umbilical serum concentrations of Ang-1 [46 (28-59) ng/mL, p < 0.0001] and Tie-2 [45 (21-71) ng/mL, p < 0.0001] were higher and those of Ang-2 similar [5.4 (1.8-18) vs. 4.2 (2.9-6.0) ng/mL; p= 0.067]. Low concentrations of Ang-1 [1.2 (0.1-2.2) ng/mL], Ang-2 [1.1 (0.3-4.1) ng/mL] and Tie-2 [0.4 (0.08-0.9) ng/mL] were observed in amniotic fluid, but they were undetectable in newborn urine and in most of the maternal urine samples. CONCLUSIONS: Maternal Ang-1 and Ang-2 concentrations decreased following delivery. Umbilical concentrations of Ang-1 and Tie-2 were higher than the maternal concentrations.

Smoking and sVEGFR-1: circulating maternal concentrations and placental expression.

Smoking reduces the expression of VEGFR-1 in non-pregnant women. In pregnant women it reduces the risk of pre-eclampsia, which in turn is associated with increased placental expression of VEGFR-1 and increased maternal circulating soluble VEGFR-1 (sVEGFR-1). We therefore hypothesized that smoking might affect VEGFR-1 expression in pregnant women. In maternal plasma sVEGFR-1 concentrations during the third trimester in both smoking (median 1088, range 834-1362ng/L, n=20) and non-smoking (728, 719-1336ng/L, n=19) women were higher than during the second trimester (smokers 374, 291-683ng/L, n=6, p>0.05; non-smokers 375, 290-667ng/L, n=22, p<0.001). No difference was observed between smokers and non-smokers. Secretion of sVEGFR-1 into the culture medium, as well as the pattern and intensity of immunostaining in first trimester placenta were similar in tissue from smoking (n=22) and non-smoking (n=20) women. Thus, contrary to our hypothesis, smoking does not affect circulating maternal sVEGFR-1 concentrations or placental secretion of sVEGFR-1 or expression of VEGFR-1 in vitro.

Maternal serum endostatin at gestational weeks 16-20 is elevated in subsequent pre-eclampsia but not in intrauterine growth retardation.

OBJECTIVE: Endostatin, an important anti-angiogenic factor produced by endothelial cells, is elevated in established pre-eclampsia. We measured maternal serum endostatin concentrations in early pregnancy associated with later pre-eclampsia and intrauterine growth retardation (IUGR). DESIGN: Retrospective case-control study. SETTING: University Central Hospital. SAMPLE: Serum samples were collected at 12-15 and 16-20 gestational weeks from a total of 124 pregnant women of whom 49 developed pre-eclampsia, 16 gave birth to infants with IUGR without pre-eclampsia, and 59 remained normotensive giving birth to healthy, normal-weight infants. METHODS: Enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Endostatin concentrations in serum. RESULTS: At 12-15 gestational weeks, there was no difference in median endostatin concentrations between the groups. At 16-20 gestational weeks, the median endostatin concentration was higher in the women with subsequent pre-eclampsia (p=0.026), especially preceding a later severe form of the disease (p=0.041), than in the controls. The results were further confirmed by receiver operating characteristic (ROC) analysis showing an area under the curve (AUC) of 0.64 (95% confidence interval: 0.50-0.81) for endostatin to identify subsequent pre-eclampsia, and 0.71 (0.53-0.89) in cases of severe pre-eclampsia. Optimal cut-off values were determined and used for calculations of sensitivity and specificity, which were 80 and 52% (cut-off value = 58.0 microg/L) in pre-eclampsia, and 80 and 65% (cut-off value = 65.5 microg/L) in the severe form of the disease. CONCLUSIONS: The concentrations of endostatin in maternal serum at 16-20 weeks' of gestation are associated with an increased risk of pre-eclampsia but not IUGR.

Concentrations of vascular endothelial growth factor C and D in amniotic fluid and maternal plasma.

OBJECTIVE: Vascular endothelial growth factor-C (VEGF-C) and VEGF-D promote both endothelial and lymphatic vascularization during embryonic development. We studied their presence in amniotic fluid (AF) and maternal plasma during pregnancy. DESIGN: Descriptive study. Setting. University Central Hospital, Helsinki, Finland. Samples. AF at 14-20 weeks (n=20) and 38-41 weeks' of gestation (n=20), serial plasma samples (n=38) from 16 healthy pregnant women during 8-40 weeks of pregnancy, and plasma from 15 non-pregnant controls. METHODS: Enzyme-linked immunosorbent assay (ELISA). Main outcome measures. Concentrations of VEGF-C and -D in AF and maternal plasma. RESULTS: VEGF-C concentrations in AF decrease as pregnancy advances (p=0.002) and are about 10-fold lower than in plasma at the corresponding gestational age (p=0.001). Plasma VEGF-C concentrations are higher in the first trimester (p=0.014) and the early second trimester (p=0.016) than in non-pregnant women. VEGF-D is not detectable in AF, but in plasma its concentrations become higher at term compared with non-pregnant women (p=0.039). CONCLUSIONS: VEGF-C and -D are present in high concentrations in maternal plasma, while only VEGF-C can be detected in AF.

Is serum-soluble vascular endothelial growth factor receptor-1 of importance in unexplained infertility?

OBJECTIVE: To analyze the role of vascular endothelial growth factor (VEGF) and its naturally occurring circulating antagonist, soluble VEGF receptor-1 (sVEGFR-1), in infertility. VEGF is a key angiogenic factor in the endometrial and ovarian cyclic processes that are crucial for fertility and sVEGFR-1 impairs its function and fertility in animals - less is known as regards human fertility. DESIGN: Case-control study. SETTING: University Central Hospital, a tertiary referral center. POPULATION: Women with unexplained infertility (n=15) and fertile controls (n=10) had serial blood samples collected during their natural cycles, and the infertile women during a subsequent in vitro fertilization (IVF) cycle. METHODS: Enzyme-linked immunosorbent assay was used for this study. MAIN OUTCOME MEASURES: Concentrations of VEGF and sVEGFR-1 in the natural cycles and of sVEGFR-1 during a subsequent IVF cycle. RESULTS: Plasma VEGF concentrations showed no cyclicity in fertile women, but were higher in the infertile group at the midluteal phase. Serum sVEGFR-1 concentrations were similar between the groups and between natural and IVF cycles. However, in infertile women, concentrations of sVEGFR-1 increased from the follicular phase to the luteal phase. In the follicular phase infertile women had a high ratio of VEGF/sVEGFR-1, which was decreased in the luteal phase. Both findings were associated with failure to achieve pregnancy in subsequent IVF cycles. CONCLUSIONS: One cause of unexplained infertility may be unbalanced secretion of sVEGFR-1 with concomitant changes in free VEGF during the transition from the follicular to the luteal phase. This aberration may be related to impaired implantation.

Maternal serum-soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation.

CONTEXT: Vascular endothelial growth factor (VEGF) promotes placental vascularization, which is inadequate in preeclampsia and intrauterine growth retardation (IUGR). The soluble receptor of VEGF (sVEGFR-1), also known as soluble fms-like tyrosine kinase-1, is produced in the placenta and reduces VEGF activity. Therefore, elevated sVEGFR-1 could contribute to the development of preeclampsia and IUGR. OBJECTIVE: The objective of this study was to study maternal serum sVEGFR-1 concentration in early pregnancy ending in preeclampsia and IUGR. DESIGN: This was a case-control study. SETTING: This study was conducted at Helsinki University Central Hospital (Helsinki, Finland), a tertiary referral center. PATIENTS: Patients included 124 pregnant women, of whom 49 developed preeclampsia, 16 gave birth to IUGR infants without preeclampsia, and 59 remained normotensive and gave birth to normal-sized infants. Serum samples were collected at 12-15 and 16-20 gestational weeks. MAIN OUTCOME MEASURES: Serum sVEGFR-1 concentrations were determined by ELISA. RESULTS: Women with subsequent preeclampsia had higher [median; interquartile range (IQR)] concentrations of sVEGFR-1 at 16-20 wk gestation (436 and 282-699 ng/liter; P = 0.005) than the controls (296 and 184-508 ng/liter). The conclusion was the same if women with mild (340 and 285-750 ng/liter; P = 0.043) or severe (497 and 235-699 ng/liter; P = 0.022) preeclampsia were analyzed separately. An elevated sVEGFR-1 concentration at 16-20 wk gestation is associated with an increased risk of preeclampsia but not of isolated IUGR. Soluble VEGFR-1 concentration decreased by 15% from the first to the second sampling in the controls but not in women with preeclampsia or IUGR. CONCLUSION: Elevated sVEGFR-1 concentrations at 16-20 wk gestation precede the clinical manifestations of preeclampsia. By neutralizing VEGF, sVEGFR-1 may contribute to inadequate placental vascularization.

Maternal serum angiopoietin-1 and -2 and tie-2 in early pregnancy ending in preeclampsia or intrauterine growth retardation.

CONTEXT: The antiangiogenic growth factor angiopoietin-2 (Ang-2) antagonizes, whereas angiopoietin-1 (Ang-1) activates the endothelial cell-specific tyrosine kinase receptor-2 (Tie-2). In preeclampsia, circulating concentrations of Ang-1 are increased and those of Ang-2 and Tie-2 are decreased. OBJECTIVE: We wanted to study whether maternal serum concentrations of Ang-1, Ang-2, and Tie-2 are altered at gestational wk 12-15 or 16-20 in women with subsequent preeclampsia or intrauterine growth retardation (IUGR). DESIGN: This was a case-control study. SETTING: The study was conducted in Helsinki University Central Hospital, a tertiary referral center. PATIENTS: This study comprised 124 pregnant women, of whom 49 developed preeclampsia and 16 gave birth to infants with IUGR, and 59 healthy women served as controls. MAIN OUTCOME MEASURES: Serum concentrations of Ang-1, Ang-2, and Tie-2 were assessed by ELISA. Data were combined with our earlier data on soluble VEGF receptor (sVEGFR)-1. RESULTS: At gestational wk 12-15, the median concentrations of Ang-1, Ang-2, or Tie-2 were all similar between the study groups. At 16-20 wk, Ang-2 concentrations were higher in women with subsequent preeclampsia [25.0 ng/ml, 19.3-39.5 ng/ml; median, interquartile range (IQR)] than in the controls (17.7 ng/ml, 10.8-27.4 ng/ml, P = 0.006). The odds ratio of high Ang-2 concentrations for subsequent preeclampsia was 4.2 (95% confidence interval 1.4-12.6; P = 0.011) and high Ang-2 combined with high sVEGFR-1, 6.4 (95% confidence interval 2.2-18.7; P = 0.001). CONCLUSION: Maternal serum Ang-2 concentrations are increased prior to preeclampsia. High concentrations of both Ang-2 and sVEGFR-1 indicate subsequent disease.