Higher sFlt-1 Levels Research Articles

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Methods A total of 24 preeclampsia was enrolled. All pregnant were Caucasian, non-smoker, BMI 30 Kg/m2. At the time of clinic attendance, venous blood samples were collected (EDTA), tubes centrifuged and plasma samples were stored at −70 °C. sFLT-1 plasma levels were measured by ELISA (DVR100B). MiRs were extracted from plasma using the miRNeasy Serum/Plasma Kit. Samples from three preeclampsia presenting the highest level of sFLT-1 and three presenting the lowest levels were choose to performed a screening using the Human Plasma miRNA PCR array (MIHS-106Z) following the manufacturer’s protocol. After screening individual miRNAs were quantified by miScript SYBR Green qRT-PCR assays using specifics primers. Results Among 84 miRNAs evaluated by PCR-array, 4 were differentially expressed between groups considering a fold-change ⩾3.0: miR-195-5p, miR-16-5p and miR-19b-3p were more expressed in high group and miR-375 in low group. The next step was performed real-time qRT-PCR in all samples (n = 24) and verify correlations with sFLT-1. We use two extremes of analysis: 50% and 25% of sFLT-1 levels in the 24 samples (n = 12 in low and n = 12 in high group considering 50% analysis; and n = 6 in low and n = 6 in high group considering 25% analysis). The result is demonstrated in Figure. Conclusions We concluded that miR195-5p is associated with higher levels of sFLT-1 in preeclampsia. Financial Support: Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). Disclosures V. Sandrim: None. K. Fernandes: None. R. Cavalli: None.

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Objectives PlGF and sFlt-1 are expressed in the trophoblast. Current data suggest increased placental production of sFlt-1 in preeclampsia. Reports diverge regarding whether the placenta is the main source of PlGF. The PlGF concentrations are lower in preeclamptic women, but it is not clear if this is a result of decreased production or increased removal from the circulation. We aimed to 1: determine if there are uteroplacental arterio-venous (av) differences of PlGF and sFlt-1 in normal pregnancies; 2: investigate if these differences are altered in preeclampsia. Methods Case-control study including 23 women with early onset (diagnosis Results As shown in the figure preeclamptic women had lower levels of PlGF and higher levels of sFlt-1 (p Conclusions The placenta seems to contribute to the higher levels of sFlt-1 found in preeclampsia. Our results suggest that the placenta delivers PlGF to the uterine circulation, but do not confirm that a placental failure of PlGF production is a key feature of preeclampsia. Disclosures A.M. Holme: None. M.P. Roland: None. M.B. Holm: None. T. Henriksen: None. T.M. Michelsen: None.

Off-pump CABG surgery reduces systemic inflammation compared with on-pump surgery but does not change systemic endothelial responses: a prospective randomized study.

Coronary artery bypass graft (CABG) surgery can result in severe postoperative organ failure. During CABG surgery, cardiopulmonary bypass (CPB) with cardiac arrest is often used (on-pump CABG), which often results in a systemic inflammatory response. To reduce this inflammatory response, off-pump CABG was reintroduced, thereby avoiding CPB. There is increasing evidence that the endothelium plays an important role in the pathophysiology of organ failure after CABG surgery. In this study, 60 patients who were scheduled for elective CABG surgery were randomized to have surgery for on-pump or off-pump CABG. Blood was collected at four time points: start, end, 6 h, and 24 h postoperatively. Levels of inflammatory cytokines, soluble adhesion molecules, and angiogenic factors and their receptors were measured in the plasma. No differences were found in preoperative characteristics between the patient groups. The levels of tumor necrosis factor-α, interleukin 10, and myeloperoxidase, but not interleukin 6, were increased to a greater extent in the on-pump CABG compared with off-pump CABG after sternum closure. The soluble endothelial adhesion molecules E-selectin, vascular cell adhesion molecule 1, and intracellular adhesion molecule 1 were not elevated in the plasma during and after CABG surgery in both on-pump and off-pump CABG. Angiopoietin 2 was only increased 24 h after surgery in both on-pump and off-pump CABG. Higher levels of sFlt-1 were found after sternum closure in off-pump CABG compared with on-pump CABG. Avoiding CPB and aortic cross clamping in CABG surgery reduces the systemic inflammatory response. On-pump CABG does not lead to an increased release of soluble endothelial adhesion molecules in the circulation compared with off-pump CABG.

Cord blood biomarkers of vascular endothelial growth (VEGF and sFlt-1) and postnatal growth: A preterm birth cohort study

BackgroundPreterm infants are at risk for postnatal growth failure (PGF). Identification of biomarkers that are associated with neonatal growth may help reduce PGF and associated long-term morbidity. ObjectiveTo investigate the associations between cord blood vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1) with birth weight (BW) and postnatal growth in premature infants. Study design and methodsFrom an ongoing birth cohort, 123 premature infants from 23 to 36 weeks gestational age (GA) were studied. Cord blood plasma VEGF and sFlt-1 were measured via enzyme-linked immunoassay. Growth parameters and nutritional information were evaluated. Multivariate logistic regression models were constructed to evaluate the associations of VEGF and sFlt-1 on PGF, defined as weight <10th percentile at 36weeks corrected age or discharge. ResultsVEGF was positively correlated, and sFlt-1 was negatively correlated with BW and BW-for-GA percentiles. Higher cord blood VEGF levels were associated with reduced risk of PGF (OR=0.7; 95% CI=0.5–0.9), while higher sFlt-1 levels appeared to increase the risk of PGF (OR=1.6; 95% CI=1.1–2.4). The above biomarker associations were attenuated after adjustment for maternal preeclampsia, fetal growth restriction and related neonatal characteristics, and when taking into account placental vascular pathologies. Longitudinal growth patterns by mean weight and length percentiles were consistently lower among infants with low VEGF/sFlt-1 ratios. ConclusionsOur data support that intrauterine regulation of angiogenesis is an important mechanism of fetal and postnatal growth. Cord blood VEGF and sFlt-1 are useful in elucidating how intrauterine processes may have long-standing effects on developing premature infants.

Soluble fms-like tyrosine kinase-1 and vascular endothelial growth factor: Novel markers for unexplained early recurrent pregnancy loss

Abstract Objective To evaluate the role of soluble fms-like tyrosine kinase-1 (sFlt-1) and vascular endothelial growth factor (VEGF) for prediction of pregnancy loss in patients with history of unexplained early recurrent pregnancy loss (RPL). Methods A prospective case control study was conducted in 42 women with history of unexplained early RPL, and 170 pregnant controls with history of uncomplicated pregnancy. We measured maternal serum sFlt-1 and VEGF at gestational age 6–9 weeks as predictor for pregnancy loss. Results Mean serum levels of sFlt-1 and VEGF were significantly higher in RPL group than controls (10439.7±385.4 vs 3304.5±104.8; P vs 709.8±24.8; P OR ) 206 [95%confidence interval ( CI ), 45.4–941]. Cutoff value of 915.5 pg/mL for VEGF was predictor for early pregnancy loss with 92.9% sensitivity, 90.6% specificity, and OR 125 [95% CI: 34.7–451]. Conclusion These data advocate a relationship between sFlt-1, VEGF, and RPL suggesting that the high levels of sFlt-1 and VEGF might be associated with the pathogenesis of RPL.

Increased Soluble Flt-1 Correlates With Delayed Graft Function and Early Loss of Peritubular Capillaries in the Kidney Graft

Ischemia-reperfusion induces tubular and endothelial damage in the renal graft and leads to delayed graft function (DGF) and to an early loss of peritubular capillaries (PTC). Few, if any, clinical studies have assessed the impact of proangiogenic and antiangiogenic factors on endothelial repair during renal transplantation (RT)-related ischemia-reperfusion. We prospectively assessed the kinetics of the antiangiogenic factor soluble Fms-like tyrosine kinase-1 (sFlt-1) in 136 consecutive RT patients and analyzed sFlt-1 impact on DGF and PTC loss. sFlt-1 plasma levels increased by twofold to threefold throughout the first week after RT. This increase was more marked in recipients of grafts from deceased donors compared with living donors. Patients with DGF had higher sFlt-1 levels at all time points during the first 7 days after RT and a higher peak sFlt-1 compared with those without DGF. In multivariate analysis, a peak plasma sFlt-1 of 250 pg/mL or higher was associated with 2.5-fold increase in the risk of DGF (P=0.04). Similarly, patients with a peak plasma sFlt-1 of 250 pg/mL or higher had a more pronounced early decrease in PTC compared with those with a peak sFlt-1 less than 250 pg/mL. sFlt-1 is a new nonimmunologic independent risk factor for DGF and PTC loss. Its inhibition may help improve the outcome of RT.

A case of PMD with the high maternal serum levels of sFlt-1

A case of PMD with the high maternal serum levels of sFlt-1

Soluble Fms-like Tyrosine Kinase 1 Is a Novel Predictor of Brain Natriuretic Peptide Elevation

Soluble fms-like tyrosine kinase 1 (sFlt-1) is an endogenous inhibitor of vascular endothelial growth factor, which is involved in cardiovascular remodeling and atherosclerosis development. To examine the predictive role of sFlt-1 levels in patients with asymptomatic heart failure, we measured circulating sFlt-1 in patients with or without coronary artery disease (CAD). We analyzed 88 Japanese patients with CAD or patients at high risk for atherosclerosis and who were undergoing total risk management for cardiovascular disease prevention. Circulating sFlt-1 levels correlated with the increase in plasma brain natriuretic peptide levels (ΔBNP) from baseline to the observed levels 5 years later in CAD patients, patients with previous myocardial infarction, and men. ΔBNP levels correlated with sFlt-1 levels in the high-sFlt-1 patients with CAD (r = 0.511, P < 0.01). In all patients, end-systolic volume index (ΔESVI) increased in correlation with a decrease in left ventricular ejection fraction (ΔEF) in the long-term observation, independent of their history of myocardial infarction (ΔESVI = 2.5 mL/m(2) increase/year). Baseline level of sFlt-1 was independent of ΔESVI or ΔEF. The present 5-year observational study demonstrated that high sFlt-1 levels predicted moderate increases in BNP levels in CAD patients. Moreover, ΔBNP was correlated with ΔESVI/year in CAD patients with high-sFlt-1 levels. These data suggest that high sFlt-1 levels may be an effective biomarker to predict the progression of heart failure in patients with CAD.

169: Are twin to twin transfusion syndrome and selective intra-uterine growth restriction a continuum? Evidence from a longitudinal study of circulating angiogenic factors

intra-uterine growth restriction a continuum? Evidence from a longitudinal study of circulating angiogenic factors Yoav Yinon, Elad Ben Meir, Boaz Weisz, Eyal Schiff, Shali Mazaki-Tovi, Shlomo Lipitz Sheba Medical Center, Tel-Aviv University, Obstetrics and Gynecology, TelHashomer, Israel OBJECTIVE: To determine maternal plasma levels of soluble fms-like tyrosine kinase-1(sFlt-1), placental growth factor (PLGF) and soluble endoglin (sEng) in monochorionic diamniotic (MC/DA) twin pregnancies complicated by twin to twin transfusion syndrome (TTTS) or selective intra-uterine growth restriction (sIUGR). STUDY DESIGN: A longitudinal cohort study of pregnant women with MC/DA twins who were classified into 3 groups: 1. Uncomplicated MC/DA twins (n 22) 2. TTTS (n 23) and 3. sIUGR (n 15). Maternal plasma samples were obtained between 13-20 and 21-28 weeks of gestation and cord blood samples were collected at delivery. Maternal plasma concentrations of sFlt-1, PLGF and sEng were measured by ELISA. RESULTS: sFlt-1 and sEng levels were significantly higher in TTTS at the early (13-20 weeks) and late (21-28 weeks) second trimester compared to normal monochorionic pregnancies (p 0.01). In contrast, sFlt-1 and sEng levels were significantly higher in the sIUGR group only at the late second trimester (p 0.05). PLGF levels were significantly lower at the early and late second trimester in both TTTS and sIUGR compared to controls (p 0.01). Plasma concentrations of sFlt-1 were significantly higher among TTTS pregnancies compared to sIUGR at the late second trimester (p 0.027). Within TTTS pregnancies who underwent fetoscopic laser ablation, the procedure resulted in elevation of PLGF levels and reduction of sFlt-1 levels. Cord blood analysis revealed significantly higher levels of sFlt-1 in the smaller IUGR twin compared to the normal co-twin. CONCLUSION: Monochorionic pregnancies complicated by TTTS and sIUGR are characterized by decreased angiogenic activity. The disparity in severity of the anti-angiogenic state between TTTS and sIUGR suggests that these two conditions may represent a continuum. Collectively, the findings reported herein shed new light on the pathophysiologic mechanisms of these severe complications of pregnancy.

Changes in circulating concentrations of soluble fms-like tyrosine kinase-1 and placental growth factor measured by automated electrochemiluminescence immunoassays methods are predictors of preeclampsia

Preeclampsia is characterized by an imbalance in angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). We herein assessed whether these factors measured by a newly developed automated electrochemiluminescence immunoassay are associated with risk to develop preeclampsia. We performed a nested case-control study within a cohort of 230 women with singleton pregnancies. The study included all 37 women who eventually developed preeclampsia and 29 normotensive controls. Serum samples were collected at 4-week intervals (from weeks 20th to 36th). sFlt-1 and PlGF were measured using a commercial automated immunoassay (Elecsys). Women destined to develop preeclampsia had lower PlGF levels and higher sFlt-1 levels and sFlt-1/PlGF ratio than women with normal pregnancies. These changes became significant at 20 weeks in women destined to develop early preeclampsia (<34 weeks, P ≤ 0.003), and at 24-28 weeks in women who later developed preeclampsia (P ≤ 0.024). The risk for developing preeclampsia was higher among women with PlGF concentration values in the lowest quartile or with sFlt-1 levels and sFlt-1/PlGF ratio in the highest quartile of the control distribution. The odds ratios were higher and appeared earlier in women destined to develop early preeclampsia than in women who presented preeclampsia later. The sFlt-1/PlGF ratio was more tightly associated with risk of preterm or term preeclampsia than either angiogenic factor alone. Changes in circulating concentrations of PlGF, sFlt-1, and in the sFlt-1/PlGF ratio precede the onset of preeclampsia. The risk profile of circulating angiogenic factors for developing preeclampsia distinctly evolves depending on whether this condition is manifested at preterm or term.

Angiogenic factors in maternal circulation and preeclampsia with or without fetal growth restriction

To study associations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in maternal circulation with the risk of preeclampsia with and without fetal growth restriction. Nested case-control study. A cohort of 29 948 pregnant women in Norway. Cases were identified through linkage to the Medical Birth Registry of Norway. We selected 69 preterm and 36 term preeclampsia cases with delivery of a small-for-gestational-age (SGA) infant, 83 preterm and 154 term preeclampsia cases without SGA delivery, and 384 normotensive controls. We measured PlGF and sFlt-1 in maternal serum samples from each trimester. Odds ratios of preeclampsia subtypes by tertile categories of PlGF and sFlt-1. Low (lowest third) PlGF and sFlt-1 levels in the first trimester, and low (lowest third) increase in PlGF and strong (highest third) increase in sFlt-1 from first to second trimester were associated with increased risk of preterm preeclampsia, both with and without SGA offspring. For term preeclampsia with SGA offspring, the associations were similar to the findings for preterm preeclampsia. For term preeclampsia without SGA offspring, low increase in PlGF from first to second trimester and high sFlt-1 in the third trimester were associated with increased risk. Low PlGF and high sFlt-1 levels in maternal circulation are associated with subsequent development of preeclampsia, regardless of whether fetal growth is affected or not. For term preeclampsia without fetal growth restriction, the imbalance in angiogenic factors seems to appear later in pregnancy than for preterm preeclampsia.

Angiogenic biomarkers for prediction of maternal and neonatal complications in suspected preeclampsia

Objective: To determine if maternal serum angiogenic factors predict maternal and neonatal complications in women presenting to an acute care setting with suspected preeclampsia. Study design: Maternal serum samples were prospectively collected from women with suspected preeclampsia at the time of initial presentation to hospital triage with signs or symptoms of preeclampsia. Soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin (sEng) were measured by ELISA. The primary outcome was a composite of maternal and neonatal complications. Results: Of 276 women with suspected preeclampsia, 78 developed maternal or neonatal complications. Among women presenting prior to 37 weeks gestation, sFlt1, PlGF, and sEng were significantly different in women who developed maternal and neonatal complications as compared to women without complications. Higher levels of sFlt1, sEng, and the sFlt1:PlGF ratio were associated with an increased odds of complications among women presenting prior to 37 weeks. A multivariable model combining the sFlt1:PlGF ratio with clinical variables was more predictive of complications (AUC 0.91, 95% CI 0.85–0.97) than a model using clinical variables alone (AUC 0.82, 95% CI 0.79–0.90). Conclusion: Angiogenic biomarkers associate with maternal and neonatal complications in women with suspected preeclampsia, and may be useful for risk stratification.

Abstract 219: Cardiac Angiogenic Imbalance Leads to Peripartum Cardiomyopathy

Peri-partum cardiomyopathy (PPCM) is a frequently fatal disease that affects women near delivery, and occurs more frequently in women with pre-eclampsia and/or multiple gestation. The etiology of PPCM, or why it associates with pre-eclampsia, remains unknown. We show here that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble Flt1 (sFlt1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by sub-clinical cardiac dysfunction, the extent of which correlates with circulating levels of sFlt1. Exogenous sFlt1 alone caused diastolic dysfunction in wildtype mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFlt1. These data strongly suggest that PPCM is in large part a vascular disease, caused by excess anti-angiogenic signaling in the peri-partum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.

PP162. sFlt-1 controlled by CPAP in a pregnant patient with chronic hypertension

Preeclampsia is recognised as the leading cause of perinatal mortality and morbidity worldwide. Interest has been increasing recently as to the possible impact of sleep disordered breathing (SDB) on the mechanisms of preeclampsia, possibly by augmenting placental hypoxia during sleep. A biomarker of preeclampsia, sFlt-1, has also come to prominence in recent years and is postulated to be a good predictor of preeclampsia as well as a strong indicator of the severity of the disease. The aim of this study was to investigate the effect of CPAP treatment for SDB on sFlt-1 concentrations during pregnancy. Patients were recruited from the outpatients' clinic in Campbelltown Hospital, Campbelltown, NSW in the first half of 2011. The levels of sFlt-1 in four pregnant women, with or without hypertensive disorders of pregnancy, and with or without SDB were measured using ELISA. Women with SDB and chronic hypertension or preeclampsia had higher levels of sFlt-1 and a greater percentage increase of this marker, and CPAP treatment appeared to attenuate the rise of sFlt-1 as shown in the table below. Elevated sFlt-1 was associated with untreated SDB in those with chronic hypertension. This study provides feasibility for a larger scale study to occur, to further examine the validity of the hypothesis that CPAP treatment has a beneficial effect on sFLt-1 levels and therefore, may lower the risk and severity of preeclampsia.

Exogenous vascular endothelial growth factor supplementation can restore the podocyte barrier‐forming capacity disrupted by sera of preeclamptic women

To determine whether exogenous vascular endothelial growth factor (VEGF) supplementation to sera from women with preeclampsia can restore the podocyte barrier-forming capacity disrupted after stimulation with sera from these women. Enzyme-linked immunosorbent assays (ELISAs) for sFlt-1 (soluble VEGF receptor 1) and VEGF were performed in the sera of preeclamptic and healthy pregnant women. VEGF-enriched preeclamptic serum was used to evaluate the capacity of such sera to restore the diminished podocyte barrier capacity secondary to stimulation with untreated preeclamptic sera. Two groups, preeclampsia (n=15) and healthy (n=15) pregnant women, were established. Median serum levels (pg/mL) of sFlt-1 and VEGF were significantly different between groups: 3987 versus 1432 and 6 versus 15.6 (P<0.001). Altered resistance values of podocytes stimulated with sera from women with preeclampsia were recovered after exogenous VEGF supplementation. The mean resistance value of cultured podocytes, an indicator of the integrity of the cytoskeleton and the capacity of these cells to form layers, is altered in women with preeclampsia. High levels of sFlt-1, an inhibitor of VEGF observed in high concentrations in the serum of these patients, could be the underlying cause of this alteration. We provide evidence that exogenous VEGF supplementation of the sera of these women could recover this indicator.

Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

Peri-partum cardiomyopathy (PPCM) is a frequently fatal disease that affects women near delivery, and occurs more frequently in women with pre-eclampsia and/or multiple gestation. The etiology of PPCM, or why it associates with pre-eclampsia, remains unknown. We show here that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble Flt1 (sFlt1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by sub-clinical cardiac dysfunction, the extent of which correlates with circulating levels of sFlt1. Exogenous sFlt1 alone caused diastolic dysfunction in wildtype mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFlt1. These data strongly suggest that PPCM is in large part a vascular disease, caused by excess anti-angiogenic signaling in the peri-partum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.

Second trimester anti-angiogenic proteins and preeclampsia

ObjectiveTo measure the relationships between soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng) and preeclampsia. Study designWe 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 measuresPreeclampsia 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±2.3weeks). ResultsDoublings 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. ConclusionsWe 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.

Excess soluble vascular endothelial growth factor receptor-1 in amniotic fluid impairs lung growth in rats: linking preeclampsia with bronchopulmonary dysplasia.

Epidemiological studies have shown that maternal preeclampsia (PE) increases the risk of bronchopulmonary dysplasia (BPD), but the underlying mechanism is unknown. Soluble vascular endothelial growth factor receptor-1 (soluble VEGFR1, known as soluble fms-like tyrosine kinase 1, or sFlt-1), an endogenous antagonist of vascular endothelial growth factor (VEGF), is markedly elevated in amniotic fluid and maternal blood in PE. Therefore, we hypothesized that antenatal exposure to excess sFlt-1 disrupts lung development through impaired VEGF signaling in utero, providing a mechanistic link between PE and BPD. To determine whether increased sFlt-1 in amniotic fluid is sufficient to cause sustained abnormalities of lung structure during infancy, sFlt-1 or saline was injected into amniotic sacs of pregnant Sprague-Dawley rats at 20 days of gestation (term, 22 days). After birth, pups were observed through 14 days of age for study. We found that intra-amniotic sFlt-1 treatment decreased alveolar number, reduced pulmonary vessel density, and caused right and left ventricular hypertrophy in 14-day-old rats. In addition, intra-amniotic sFlt-1 treatment suppressed activation of lung VEGF receptor-2 and increased apoptosis in endothelial and mesenchymal cells in the newborn lung. We conclude that exposure to excess sFlt-1 in amniotic fluid during late gestation causes sustained reductions in alveolarization and pulmonary vascular growth during infancy, accompanied by biventricular hypertrophy suggesting pulmonary and systemic hypertension. We speculate that impaired VEGF signaling in utero due to exposure of high amniotic fluid levels of sFlt-1 in PE disrupts lung growth and contributes to the increased risk of BPD in infants born to mothers with PE.

Fetal endothelium dysfunction is associated with circulating maternal levels of sE-selectin, sVCAM1, and sFlt-1 during pre-eclampsia

Objectives. To evaluate the association between endothelial activation markers in the maternal circulation with nitric oxide (NO) synthesis in human umbilical endothelial cells.Study design. This is a case-control study of normal and pre-eclamptic pregnancies. The levels of sE-selectin, soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble fms-like tyrosine kinase 1 (sFlt-1) were measured by enzyme-linked immunosorbent assay, and histamine-induced NO synthesis was detected by fluorometric examination of the human umbilical vein endothelial cells (HUVECs) isolated from normal and pathological pregnancies.Results. Mothers with severe pre-eclamptic pregnancies have premature and smaller babies than mothers with normal pregnancies (P < 0.05); they also have high maternal plasma levels of sVCAM-1 (∼2-fold), sFlt-1 (∼2.5-fold), and lower (∼70%) histamine-stimulated NO synthesis in HUVECs. A positive relationship between systolic blood pressure (SBP) and plasma levels of sE-selectin, sVCAM-1, and sFlt-1 was demonstrated. Moreover, levels of sE-selectin, sVCAM-1, and sFlt-1 were negatively associated with newborn weight (NBW), gestational age at delivery, and NO synthesis. Women with high E-selectin (>63 ng/ml), VCAM-1 (>752 ng/ml), and sFlt-1 (>15204 pg/ml) showed high risk (∼2-fold) for preterm delivery and very preterm delivery, or fetal weight <1500 g (∼1.5-fold) compared with women with low levels.Conclusions. High circulating levels of maternal endothelial dysfunction markers present in pre-eclampsia are associated with decreased NO synthesis in fetal endothelium.

P118 Umbilical vein endothelium activation is associated with high maternal levels of sE-selectin, sVCAM-1 and sFlt-1 in severe pre-eclamptic pregnancies

P118 Umbilical vein endothelium activation is associated with high maternal levels of sE-selectin, sVCAM-1 and sFlt-1 in severe pre-eclamptic pregnancies