Placental Growth Factor Concentrations Research Articles

Absence of placental growth factor blocks dextran sodium sulfate-induced colonic mucosal angiogenesis, increases mucosal hypoxia and aggravates acute colonic injury

Angiogenesis has recently been described as a component of inflammatory bowel disease. Placental growth factor (PlGF), a vascular endothelial growth factor (VEGF) homologue, establishes its angiogenic capacity under pathophysiological conditions. We investigated the function of PlGF in experimental models of acute colitis. Acute colonic damage was induced in PlGF knock-out (−/−) mice and PlGF wild-type (+/+) mice by dextran sodium sulfate (DSS) and trinitrobenzenesulfonic acid (TNBS). The concentrations of PlGF and VEGF were measured in distal colonic lysates using an enzyme-linked immunosorbent assay. Colonic injury was evaluated by assessing colon length, colonocyte apoptosis (by terminal dUTP nick-end labeling), colonic cytokine production and histological score. Infiltration of polymorphonuclear cells was determined by assaying myeloperoxidase (MPO) activity. In a separate experiment, recombinant PlGF was administered to PlGF−/− mice by adenoviral transfer before DSS administration. Mucosal vascularization was quantified by computerized morphometric analysis of CD31-stained distal colonic sections. Colonic mucosal hypoxia was visualized by pimonidazole staining. Both VEGF and PlGF were upregulated during acute colitis. In addition, compared with PlGF+/+ controls, PlGF−/− mice showed a significant increase in weight loss and colonic shortening during both DSS and TNBS colitis. This correlated with enhanced colonocyte apoptosis, elevated colonic cytokine levels and increased histological damage score, but not with enhanced inflammatory cell infiltration (MPO activity). The increased morbidity of PlGF−/− mice during DSS colitis was preventable by adenovirus (Ad)-mediated overexpression of PlGF. After the administration of DSS, strongly reduced mucosal angiogenesis was observed in PlGF−/− mice compared with PlGF+/+ mice. This was associated with an early increase in intestinal epithelial pimonidazole accumulation in PlGF−/− mice, suggesting a function of enhanced epithelial hypoxia in the observed differences between the two groups. In summary, our data show that the absence of PlGF strongly inhibits mucosal intestinal angiogenesis in acute colitis, which is associated with an early increase in intestinal epithelial hypoxia and aggravation of the course of the disease.

Modification of angiogenic factors by regular and acute exercise during pregnancy

This cross-sectional study examined mechanisms through which exercise might alter preeclampsia risk by estimating the effects of acute and chronic exercise on angiogenic markers in healthy pregnant women with different amounts of regular exercise participation. Serum-soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) were measured before and after 20 min of moderate-intensity cycle ergometry in normotensive, nonsmoking pregnant (16 active, 9 inactive, 34.1+/-1.6 wk gestation) and nonpregnant (15 active, 12 inactive, midlate luteal phase) women. Inactive women did not regularly exercise at an intensity that was sufficient to cause sweating. Active women exercised for at least 3 h/wk. Inactive pregnant women had significantly lower PlGF concentrations [median (interquartile range): 268 (159, 290) vs. 278 (221, 647) pg/ml, P=0.014] and higher sFlt-1 [5,180 (4,540, 5,834) vs. 4,217 (2,014, 5,481) pg/ml, P=0.005] and sEng concentrations [9.1 (7.7, 16.7) vs. 7.8 (6.5, 10.1) ng/ml, P=0.025] than active pregnant women. This effect of regular exercise participation was not observed in nonpregnant women. Acute exercise in pregnancy was not associated with antiangiogenic changes that might contribute to preeclampsia; rather, there was a small, but statistically significant, increase in PlGF following acute exercise in active pregnant women [278 (221, 647) vs. 335 (245, 628) pg/ml, P=0.014]. sFlt-1 increased significantly following acute exercise in inactive nonpregnant women [90 (86, 100) vs. 106 (101, 116) pg/ml, P=0.012], but not in active nonpregnant women. Regular exercise during pregnancy is associated with higher serum PlGF and lower sFlt-1 and sEng concentrations in late gestation, a difference that is unlikely to have predated the pregnancy.

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. Nonparametric 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.

Acute pyelonephritis during pregnancy changes the balance of angiogenic and anti-angiogenic factors in maternal plasma

Objective. Angiogenic factors have been implicated in the pathophysiology of sepsis. In experimental models of sepsis (endotoxemia and/or cecal ligation puncture), there is increased expression of vascular endothelial growth factors (VEGF) and the administration of exogenous soluble VEGF receptor (sVEGFR)-1, an antagonist to VEGF, reduces morbidity and mortality. Moreover, a dramatic elevation in sVEGFR-1 has been demonstrated in human sepsis. Although a balance between angiogenic and anti-angiogenic factors is essential for feto-placental development, the changes of angiogenic factors during pregnancy in the context of infection have never been explored. Angiogenic factors also play crucial roles in the pathophysiology of preeclampsia (PE). This study was conducted to determine if maternal plasma concentrations of placental growth factor (PlGF), sVEGFR-2, and soluble endoglin (sEng) change in pregnancies complicated by acute pyelonephritis (AP) compared with normal pregnancy and PE.Study design. A case-control study was conducted in patients with AP, normal pregnant (NP) women, and patients with PE (n = 36 for each group) matched for gestational age. AP was diagnosed in the presence of fever (temperature ≥38°C), clinical signs of infection, and a positive urine culture for microorganisms. Plasma concentrations of PlGF, sVEGFR-2, and sEng were determined by ELISA. The results of plasma sVEGFR-1 concentrations have previously been reported, but were included in this study to provide a complete picture of the angiogenic/anti-angiogenic profiles. Serum concentrations of interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, interferon (IFN)-γ, granulocyte macrophage colony stimulating factor, and tumor necrosis factor (TNF) were also determined using high sensitivity multiplexed immunoassays in patients with AP and NP.Results. AP was associated with a lower median plasma concentration of PlGF and sVEGFR-2 than NP (both p < 0.001). There were no significant differences in the median plasma concentrations of sEng and sVEGFR-1 between AP and NP (p = 0.7 and 0.5, respectively). In contrast, there was a 5-fold decrease of the median plasma concentration of PlGF, and an 8–10-fold increase of the median plasma concentrations of sVEGFR-1 and sEng in PE compared with those in AP (all p < 0.001). No significant difference in the median plasma concentration of sVEGFR-2 was observed between patients with PE and AP (p = 0.5). Pregnant women with AP had median plasma concentrations of IL-6, IL-7, IL-8, IL-10, IFN-γ, and TNF-α significantly higher than those in NP women (all p < 0.001, except IL-7 p = 0.004).Conclusion. AP is associated with changes in the profile of angiogenic and anti-angiogenic factors. Although some of these changes resemble those in PE (decreased PlGF and sVEGFR-2), the magnitude of the changes of PlGF is much higher in PE. We conclude that despite high plasma inflammatory cytokine concentrations, acute systemic inflammation in pregnancy has a different angiogenic/anti-angiogenic profile than that of PE.

The sFLT-1 to PlGF Ratio is Impaired in Patients with Thalassemia and Sickle Cell Disease.

Abstract 2010Poster Board I-1032 Background:Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is associated with inflammation and with pathologic angiogenesis. PlGF is released from marrow erythroid cells. Serum PlGF concentrations have been reported to be elevated in patients with sickle cell disease. The fms-like tyrosine kinase-1 or sFlt-1 is a soluble form of vascular endothelial growth factor receptor-1 (VEGF-R1), which binds to and sequesters circulating free vascular endothelial growth factor (VEGF) and free PlGF, thereby neutralizing their pro-angiogenic effects. PlGF and VEGFR-1 are key molecules in regulating the angiogenic switch during pathological conditions maintaining the proangio-and anti-angiogenic balance. Perturbations of this balance leads to various degree of endothelial dysfunction, a common pathology in patients with hemoglobinopathies and specifically induce pulmonary hypertension (PHT). In this study we assessed the PlGF and sFLT-1 levels in patients with hemoglobinopathies at steady state. Patients and Methods:One hundred twenty three patients with hemoglobinopathies and 20 apparently healthy individuals were included in the study divided in groups as follows: Group A: 38 patients with thalassemia intermedia; Group B: 41 patients with transfusion-dependent beta-thalassemia; Group C: 33 patients with beta-thallassemia/sickle cell disease (SCD) Group D: 11 patients with beta-thallassemia and clinical evidence of PHT, and; Group E: 20 individuals served as control group In patients and controls we performed measurements of PlGF and sFLT-1 with fully automated electrochemiluminescence assays using the immunochemistry autoanalyzer Roche cobas e411. This method provides rapid and reliable assessments and follow-up of patients any time in the day compared to immunoenzymatic assays. Results:We found that: a) serum PlGF levels were increased in all groups of patients compared to controls (42.7±19.9 pg/mL, 49.9±23.4 pg/mL, 27.5±9.4 pg/mL, 58.1±27.6 pg/mL for group A, B, C and D, respectively vs 17.1±3.9 pg/mL for control group, p<0.001), b) serum sFLT-1 levels were also increased in all groups of patients compared to controls (89.3±18.3 pg/mL, 90.2±24.0 pg/mL, 89.4±15.3 pg/mL, 117.2±43.5 pg/mL, respectively vs 76.7±11.1 pg/mL, p<0.001 for control group and c) sFLT-1 to PlGF ratio was decreased in all groups of patients compared to controls (2.4±0.9, 2.2±1.2, 3.5±1.0, 2.2±0.8, respectively vs 4.7±1.1 for control group, p<0.001. The most significant changes were found in patients with PHT. Conclusions:These findings indicate that patients with thalassemia syndromes and SCD appear to have increased degree of angiogenesis, which is more pronounced in patients with thalassemia compared to patients with SCD and markedly increased in patients with PHT. The decreased sFLT-1/PlGF ratio in almost all patients suggest that the proangio-and anti-angiogenic system is shifted towards to proangiogenic state, providing evidence that patients with hemoglobinopathies even in the steady phase have altered angiogenic state and low-grade inflammation. The results are in accordance to those published earlier for SCD (Blood, 2008;112:856-865.), where the authors demonstrated that PlGF levels were intrinsically elevated due to the increased red cell turnover and may contribute to inflammation and PHT seen in the disease. Disclosures:No relevant conflicts of interest to declare.

A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia

Objective. Changes in the maternal plasma concentrations of angiogenic (placental growth factor (PlGF) and vascular endothelial growth factor (VEGF)) and anti-angiogenic factors (sEng and vascular endothelial growth factor receptor-1 (sVEGFR-1)) precede the clinical presentation of preeclampsia. This study was conducted to examine the role of maternal plasma PlGF, sEng, and sVEGFR-1 concentrations in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.Methods. This longitudinal cohort study included 1622 consecutive singleton pregnant women. Plasma samples were obtained in early pregnancy (6–15 weeks) and midtrimester (20–25 weeks). Maternal plasma PlGF, sEng, and sVEGFR-1 concentrations were determined using sensitive and specific immunoassays. The primary outcome was the development of preeclampsia. Secondary outcomes included term, preterm, and early-onset preeclampsia. Receiving operating characteristic curves, sensitivity, specificity, positive and negative likelihood ratios, and multivariable logistic regression were applied. A p-value of <0.05 was considered significant.Results. (1) The prevalence of preeclampsia, term, preterm, (<37 weeks) and early-onset preeclampsia (<34 weeks) was 3.8 (62/1622), 2.5 (40/1622), 1.4 (22/1622) and 0.6% (9/1622), respectively; (2) Higher likelihood ratios were provided by ratios of midtrimester plasma concentrations of PlGF, sEng, and sVEGFR-1 than single analytes; (3) Individual angiogenic and anti-angiogenic factors did not perform well in the identification of preeclampsia as a whole; in particular, they perform poorly in the prediction of term preeclampsia; (4) In contrast, a combination of these analytes such as the PlGF/sEng ratio, its delta and slope had the best predictive performance with a sensitivity of 100%, a specificity of 98–99%, and likelihood ratios for a positive test of 57.6, 55.6 and 89.6, respectively, for predicting early-onset preeclampsia.Conclusions. (1) The PlGF/sEng ratio and its delta and slope had an excellent predictive performance for the prediction of early-onset preeclampsia, with very high likelihood ratios for a positive test result and very low likelihood ratios for a negative test result; and (2) Although the positive likelihood ratios are high and the positive predictive values low, the number of patients needed to be closely followed is 4:1 for the PlGF/sEng ratio and 3:1 for the slope of PlGF/sEng.

Dysregulation of anti-angiogenic agents (sFlt-1, PLGF, and sEndoglin) in preeclampsia—a step forward but not the definitive answer

Preeclampsia (PE) is a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, which resolves on placental delivery. It is thought to be the consequence of impaired placentation due to inadequate trophoblastic invasion of the maternal spiral arteries. In PE the maternal plasma concentration of free vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) is decreased whereas the concentration of soluble fms-like tyrosine kinase-1 (sFlt-1) and of soluble endoglin (sEng) is increased. These soluble receptors may bind VEGF, PLGF and TGFbeta1 and TGFbeta3 in the maternal circulation, causing endothelial dysfunction in many maternal tissues. Hence there is a view that the pathogenesis is more or less clarified. According to the vascular theory, poor placentation leads to poor uteroplacental perfusion and hypoxia, which stimulates sFlt-1 and sEng production causing the maternal syndrome. This assumption has been recently challenged. The role of hypoxia as the main stimulus for release of sFlt-1 has been questioned and the role of inflammatory mechanisms has been emphasized. According to this inflammatory theory, poor placentation may predispose more to placental oxidative stress than hypoxia and endothelial dysfunction may be part of a broader disorder of systemic inflammation. Finally, the recent demonstration of activating auto-antibodies to the angiotensin 1 receptor that experimentally play a major pathogenic role in PE further suggests a pleiotropism of aetiologies for this condition. The purpose of this review is to critically evaluate the recent hypotheses and their possible insights on early diagnosis, prevention and treatment.

Angiogenic Balance in Pregnancy and Subsequent Breast Cancer Risk and Survival: A Population Study

Women with a history of preeclampsia have reduced breast cancer risk. Because preeclampsia is characterized by an imbalance in angiogenic factors, we assessed pregnancy levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (s-endoglin) and subsequent breast cancer risk. In a case-control study among 26,744 pregnant women, we compared angiogenic factors between 145 women who later developed invasive breast cancer and 400 controls. The angiogenic factors were determined with ELISA in blood samples collected in weeks (median) 10, 23, and 35 of the baseline pregnancy. Concentrations of PlGF, sFlt-1, and s-endoglin did not differ between women who later developed breast cancer and control women, and odds ratios across quartiles of each factor did not indicate any association in blood samples from gestational week 10, 23, or 35. During pregnancy, there was a general increase in each angiogenic factor, but degree of increase from one sampling period to the next was not associated with later breast cancer risk. Among cases, 22 of 145 died from breast cancer during 10 years of follow-up, but there was no consistent indication that angiogenic factors measured in pregnancy up to several years before diagnosis were associated with case fatality. The results of this nested case-control study, based on blood samples collected up to three time points during pregnancy, and subsequent cancer follow-up, do not provide any evidence that pregnancy levels of PlGF, sFlt-1, and s-endoglin are associated with breast cancer risk later in life.

First trimester urinary placental growth factor and development of pre‐eclampsia

To compare urinary placental growth factor (PlGF) concentration at 11(+0) to 13(+6) weeks of gestation in women who subsequently develop pre-eclampsia with normotensive controls. Nested case-control study within a prospective study for first trimester prediction of pre-eclampsia. Routine antenatal visit in a teaching hospital. Fifty-two women who developed pre-eclampsia and 52 controls matched for gestational age and sample storage time. Urinary PlGF concentration and PlGF to creatinine ratio were measured in women who developed pre-eclampsia and their matched controls. Comparisons between groups were performed using Student's t test. Development of pre-eclampsia. In the pre-eclampsia group, the median urinary PlGF concentration (20.6 pg/ml, interquartile range [IQR] 9.1-32.0 pg/ml) and median urinary PlGF to creatinine ratio (1.6 pg/mg, IQR 1.2-2.5 pg/mg) were not significantly different from the control group (11.8 pg/ml, IQR 5.5-29.8 pg/ml, P=0.1 and 1.7 pg/mg, IQR 1.2-2.3 pg/mg, P=0.3, respectively). There were no significant differences between women with early-onset pre-eclampsia requiring delivery before 34 weeks (n=13) and those with late-onset pre-eclampsia (n=39) and between women with pre-eclampsia and fetal growth restriction (FGR) (n=25) and those with pre-eclampsia and no FGR (n=27) in either median PlGF concentration or median urinary PlGF to creatinine ratio. The development of pre-eclampsia is not preceded by altered urinary PlGF concentration in the first trimester of pregnancy.

Maternal serum placental growth factor at 11–13 weeks in chromosomally abnormal pregnancies

To investigate the potential value of maternal serum placental growth factor (PlGF) in first-trimester screening for trisomy 21 and other major chromosomal abnormalities. The maternal serum concentration of PlGF at 11 + 0 to 13 + 6 weeks was measured in 609 euploid and 175 chromosomally abnormal pregnancies, including 90 with trisomy 21, 28 with trisomy 18, 19 with trisomy 13, 28 with Turner syndrome and 10 with triploidy. The levels of PlGF were compared in cases and controls, and were assessed for association with free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Logistic regression analysis demonstrated in the euploid group that significant independent contributions for log PlGF were provided by fetal crown-rump length, maternal weight, cigarette smoking and ethnic origin; after correction for these variables the median multiple of the median (MoM) PlGF was 0.991. Significantly lower values were observed in pregnancies with trisomy 21 (0.707 MoM), trisomy 18 (0.483 MoM), trisomy 13 (0.404 MoM), triploidy (0.531 MoM) and Turner syndrome (0.534 MoM). Significant contributions in the prediction of trisomy 21 were provided by maternal age, serum PlGF, PAPP-A and free beta-hCG, and the detection rates of screening with the combination of these variables were 70% and 80% at respective false-positive rates of 3% and 5%. Maternal serum PlGF concentration at 11-13 weeks of gestation is potentially useful in first-trimester screening for trisomy 21 and other major chromosomal abnormalities.

Elevated serum soluble fms-like tyrosine kinase 1 (sFlt1) level in women with hydatidiform mole

To show soluble fms-like tyrosine kinase 1 (sFlt1) levels in sera from patients with hydatidiform mole, which is known to predispose women to severe early-onset preeclampsia. Comparative study. University hospital and surrounding community hospitals. Seven women with pathologically diagnosed complete hydatidiform mole (mole group), 21 gestational- and maternal-age-matched women who did not develop any pregnant complication during their pregnancy (control group), and eight women who subsequently developed preeclampsia (preclinical preeclampsia group). Blood samples were taken before and after evacuations of hydatidiform mole. Concentrations of sFlt1 and free placental growth factor (PlGF) in serum were measured by ELISA. Serum sFlt1 concentrations were significantly higher in the mole group compared with the control group and the preclinical preeclampsia group. In contrast, serum free PlGF concentrations were significantly lower in the mole group. In the mole group, there was a significant negative correlation between sFlt1 and PlGF serum concentrations. After the evacuation of hydatidiform mole, the level of serum sFlt1 decreased dramatically. Elevated levels of sFlt1 were noted in molar gestations and may play in a role in early-onset preeclampsia reported in such pregnancies.

Increased circulating placental growth factor during percutaneous coronary intervention is associated with applied radiocontrast agent

Recent studies have suggested placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) as promising new biomarkers for risk stratification in acute coronary syndromes (ACS). However, little is known about the influence of percutaneous coronary intervention (PCI) on circulating PlGF and VEGF levels. Thirty-five patients with ACS, 27 patients with stable coronary artery disease (sCAD), and nine healthy controls were enrolled in the study. Although all patients with ACS and 14 patients with stable angina pectoris underwent PCI, 13 patients with coronary artery disease required no revascularization (sCAD). PlGF and VEGF plasma concentrations were measured by immunoassay during and at the end of PCI and coronary angiography. Plasma PlGF levels were comparable in patients with ACS and sCAD on admission. Although coronary angiography or heparin alone did not alter PlGF and VEGF levels, immediately after PCI a dramatic increase was seen in circulating PlGF and a decrease in VEGF, which was independent of the clinical presentation of the patients, heparin administration, or the angiographic procedure itself, but was associated with the extent of coronary artery disease and the amount of the injected contrast media. In-vitro experiments revealed that radiocontrast agents induced the release of PlGF from endothelial cells without altering PlGF mRNA expression. Patients undergoing PCI exhibit an increase in circulating PlGF, probably caused by posttranslational modifications of radiocontrast agents in endothelial cells. Therefore, analysis of plasma PlGF and VEGF levels may consider the timing of blood sampling with respect to PCI and contrast media exposure.

The relationship of the level of circulating antiangiogenic factors to the clinical manifestations of preeclampsia

This study investigated whether the antiangiogenic factors' concentrations differ according to the clinical manifestations of preeclampsia. This study included 62 preeclampsia and compared the soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), and placental growth factor (PlGF) concentrations among patients with different clinical manifestations of preeclampsia. We also compared the patients with preeclampsia to 62 controls matched by age, gestational age, and parity after 20 weeks of gestation. The sEng concentrations were significantly elevated in early-onset than in late-onset preeclampsia (105.4 +/- 37.9 vs 66.3 +/- 36.0 ng/mL, p = 0.0008). Moreover, the sEng levels were also higher in severe preeclampsia compared to mild (42.5 +/- 31.0 vs 79.2 +/- 38.6 ng/mL, p = 0.0013) and in the small for gestational age (SGA) group compared to the group without SGA (68.3 +/- 39.3 vs 85.7 +/- 38.2 ng/mL, p = 0.0273). The sFlt-1 levels, however, did not reveal significant difference according to the onset-time, severity, and presence of SGA. The antiangiogenic factors' concentrations were not related with the degree of hypertension or proteinuria. Altered antiangiogenic factors might be involved in the pathogenesis of preeclampsia with synergistic, but different roles. Especially, sEng may be more related with early and severe preeclampsia.

High Serum Level of Placental Growth Factor (PlGF) Predicts Adverse Overall Survival in Patients with Acute Myeloid Leukemia Treated with Standard Chemotherapy

Background: Angiogenesis plays an important role in the pathogenesis of acute myeloid leukemia (AML) and vascular endothelial growth factor (VEGF) is an essential positive regulator of this process. Placental growth factor (PlGF) is a member of VEGF family that exerts its angiogenic action by synergizing with VEGF. There is also evidence that PlGF may be survival factor for angiogenic endothelial cells. The role of PlGF in patients with acute leukemia have not been investigated at all.Material and methods: We measured the plasma concentrations of VEGF and PlGF in 61 patients with newly diagnosed AML and 22 healthy controls using the ELISA assay. Additionally, in AML patients we correlated the plasma levels of angiogenic cytokines with the number of viable (CEC) and apoptotic (CECAnnV+) circulating endothelial cells, known prognostic factors, response to induction therapy as well as overall survival (OS). The AML group consisted of 34 women and 27 men with a median age of 49 years (range 25–76 years). All patient received standard induction chemotherapy (according to 3+7 protocol). Statistical analysis included the following variables: VEGF and PlGF levels, age, sex, performance status, cytogenetic risk group according SWOG, presence of multilineage dysplasia, WBC and PLT count, hemoglobin level, LDH activity, % of bone marrow blasts and CEC as well as CECAnnV+ number.Results: The PlGF and VEGF median levels (23,6 pg/ml and 45,1 pg/ml respectively) were significantly higher in the AML at diagnosis than in the healthy subjects (9,5 pg/ml; p<0,0001 and 25,2 pg/ml; p<0,03 respectively). Moreover, the VEGF level at diagnosis in patients who did not respond to induction chemotherapy was significantly higher than in patients who achieved complete remission (CR) (84,7 vs 31,2 pg/ml; p<0,01). The significant negative correlation between the VEGF and percentage of apopototic CECAnnV+ was also observed.Median follow-up was 12,1 months (range: 1– 43 months). 50 patients (82%) achieved CR. The CR rate in low and high VEGF expressors was respectively 86% and 70% (p=0.07). The CR rate in high- and low PlGF expressors did not differ significantly (74% and 80% respectively). In univariate analysis poor cytogenetics was the only factor associated with increased risk of treatment failure. The median time of OS in analysed group was 15 months. In the univariate analysis high (over median) PlGF levels was associated with shorter OS (p=0.005) (Figure1).Shorter OS was also associated with age>40 years (p=0.009), failure to achieve CR (p=0.009) and higher (>50%) bone marrow infiltration with leukemic blasts (p=0.005). In the multivariate Cox proportional hazard model the elevated PlGF plasma level was strongly associated with shorter OS (p<0.007). The other factors found to influence shorter OS were: high bone marrow infiltration with leukemic blasts (p=0.02), age>40 years (p=0.04), failure to achieve CR (p=0.04).Conclusions: In conclusion we can state that the high plasma concentration of PlGF is associated with poor prognosis in AML patients. Observed in our study significantly higher PlGF level in AML patients compared to healthy controls may indicate that this angiogenic cytokine plays an important, independent of VEGF role in pathogenesis of AML [Display omitted]

Maternal serum placental growth factor (PlGF) in small for gestational age pregnancy at 11+0 to 13+6 weeks of gestation

To investigate the pathogenesis of pregnancies delivering small for gestational age (SGA) neonates by examining biochemical and Doppler indices of placental development during the first trimester of pregnancy. The concentration of placental growth factor (PlGF) at 11(+0)-13(+6) weeks was measured in 296 cases, which delivered SGA neonates, and 609 controls. The newborn was considered to be SGA if the birth weight was less than the fifth percentile after correction for gestation at delivery and sex, maternal racial origin, weight, height and parity. The distributions of uterine artery pulsatility index (PI), PlGF and PAPP-A, expressed in multiples of the median (MoM), in the control and SGA groups were compared. Logistic regression analysis was used to determine if significant contribution is provided by maternal factors, PlGF, PAPP-A and uterine artery PI in predicting SGA. The median PlGF (0.900 MoM) and PAPP-A (0.778 MoM) were lower and uterine artery PI was higher (1.087 MoM) in the SGA group than in the controls (PlGF: 0.991 MoM; PAPP-A: 1.070 MoM; uterine artery PI: 1.030 MoM). In the SGA group there was a significant association between PlGF and PAPP-A (r = 0.368, p < 0.0001) and uterine artery PI (r = 0.191, p = 0.001). Significant contributions for the prediction of SGA were provided by maternal factors, PlGF and PAPP-A and with combined screening the detection rate was 27% at a false-positive rate of 5%. Birth weight is predetermined by placental development during the first trimester of pregnancy.

Placental growth factor attenuates suppression of erythroid colony formation by interferon

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is associated with inflammation and with pathologic angiogenesis. PlGF is released from marrow erythroid cells, and serum PlGF concentrations have been reported to distinguish sickle cell patients from healthy controls. We observed that erythroid colony forming units (CFU-Es) from homozygous sickle cell (SS) patients are less sensitive to inhibition by rhgammaIFN than those from healthy controls, and the contribution of PlGF to this process was evaluated. At 10-1000-pg/mL concentrations, PlGF neither inhibits nor enhances CFU-E colony formation, and no differences were observed between the responses of SS patients or healthy controls. rhPlGF 100 pg/mL reversed the inhibitory effects of rhgammaIFN on CFU-E colony formation. rhPlGF significantly attenuated rhgammaIFN induction of the Fas ligand in an erythroid cell line (HCD57). Both HCD57 cells and CD36+ human marrow cells express Flt-1, which is a receptor for PlGF. A neutralizing antibody against Flt-1 partially attenuated the IFN-protective effect of rhPlGF, although this effect was not statistically significant. In conclusion, increased PlGF concentrations in the marrow of SS patients may protect erythroid progenitors from cytokine-induced inhibition of colony formation, and it may be a mechanism by which erythropoiesis in sickle cell disease is preserved despite concurrent inflammation.

Maternal serum placental growth factor at 11 + 0 to 13 + 6 weeks of gestation in the prediction of pre‐eclampsia

To investigate the potential value of maternal serum placental growth factor (PlGF) in first-trimester screening for pre-eclampsia (PE). The concentration of PlGF at 11 + 0 to 13 + 6 weeks' gestation was measured in samples from 127 pregnancies that developed PE, including 29 that required delivery before 34 weeks (early PE) and 98 with late PE, 88 cases of gestational hypertension (GH) and 609 normal controls. The distributions of PlGF multiples of the median (MoM) in the control and hypertensive groups were compared. Logistic regression analysis was used to determine the factors with a significant contribution for predicting PE. In the control group significant independent contributions for log PlGF were provided by fetal crown-rump length, maternal weight, cigarette smoking and racial origin, and after correction for these variables the median MoM PlGF was 0.991. In the early-PE and late-PE groups PlGF (0.611 MoM and 0.822 MoM, respectively; P < 0.0001) and pregnancy-associated plasma protein-A (PAPP-A) (0.535 MoM; P < 0.0001 and 0.929 MoM; P = 0.015, respectively) were reduced but in GH (PlGF: 0.966 MoM; PAPP-A: 0.895 MoM) there were no significant differences from controls. Significant contributions for the prediction of PE were provided by maternal characteristics and obstetric history, serum PlGF and uterine artery pulsatility index (PI) and with combined screening the detection rates for early PE and late PE were 90% and 49%, respectively, for a false-positive rate of 10%. Effective screening for PE can be provided by a combination of maternal characteristics and obstetric history, uterine artery PI and maternal serum PlGF at 11 + 0 to 13 + 6 weeks' gestation.

Maternal endothelial function and serum concentrations of placental growth factor and soluble endoglin in women with abnormal placentation

To determine whether maternal serum concentrations of placental growth factor (PlGF) and soluble endoglin (sEng) are altered in women who subsequently develop pre-eclampsia (PE) or have small-for-gestational-age (SGA) infants, and whether these changes are associated with maternal endothelial dysfunction. Maternal serum PlGF and sEng were measured in two groups of pregnant women at 23-25 weeks' gestation: Group A (n = 40), with normal uterine artery Doppler waveforms and Group B (n = 43) with abnormal Doppler. Maternal endothelial dysfunction was assessed by flow-mediated dilatation (FMD) of the brachial artery. Comparisons between groups were performed using one-way analysis of variance. In Group B, 16 women had normal outcome, 15 delivered SGA infants and 12 developed PE. Women who developed PE had lower levels of PlGF (154.8 +/- 150.8 vs. 423.3 +/- 230.5 pg/mL; P < 0.001) (data given as mean +/- SD) and higher levels of sEng (8.1 (7.0-14.1) vs. 6.5 (4.9-7.9) pg/mL; P < 0.05) (data given as median (interquartile range)) than Group A. Similar were the findings in women who delivered SGA infants. In women who subsequently developed PE, there was no correlation between FMD and either PlGF or sEng. Maternal serum concentrations of PlGF and sEng are altered in women who develop PE. However, these alterations do not correlate directly with maternal endothelial dysfunction.

Blood pressure augmentation and maternal circulating concentrations of angiogenic factors at delivery in preeclamptic and uncomplicated pregnancies

The objective of the study was to determine whether blood pressure increases are associated with maternal angiogenic factors in uncomplicated and preeclamptic pregnancies. 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. 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. 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.

Placental Growth Factor and Vascular Endothelial Growth Factor Receptor-2 in Human Lung Development

We examined the pulmonary expression of 2 proangiogenic factors, namely, placental growth factor and vascular endothelial growth factor receptor-2, during lung development and acute and chronic lung injury in newborn infants. Six groups were included in an immunohistochemical study of placental growth factor and vascular endothelial growth factor receptor-2, that is, 9 fetuses, 4 preterm and 8 term infants without lung injury who died soon after birth, 5 preterm infants with respiratory distress syndrome of <2 days and 7 with respiratory distress syndrome of >10 days, and 6 with bronchopulmonary dysplasia. Placental growth factor concentrations in tracheal aspirate fluid were measured in 70 samples from 20 preterm infants during the first postnatal week. In immunohistochemical analyses, placental growth factor staining was seen in bronchial epithelium and macrophages in all groups. Distal airway epithelium positivity was observed mostly in fetuses and in preterm infants who died soon after birth. Vascular endothelial growth factor receptor-2 staining was seen in vascular endothelium in all groups and also in lymphatic endothelium in fetuses. Vascular endothelial growth factor receptor-2 staining in arterial endothelium was associated with higher and staining in venous endothelium with lower gestational age. In capillaries, less vascular endothelial growth factor receptor-2 staining was seen in bronchopulmonary dysplasia. The mean placental growth factor protein concentration in tracheal aspirate fluid during the first postnatal week was 0.64 +/- 0.42 pg/mL per IgA-secretory component unit. Concentrations during the first postnatal week were stable. Lower placental growth factor concentrations correlated with chorioamnionitis and lactosyl ceramide positivity. The vascular endothelial growth factor receptor-2 staining pattern seems to reflect ongoing differentiation and activity of different endothelia. Lower vascular endothelial growth factor receptor-2 expression in capillary endothelium in bronchopulmonary dysplasia might be a reflection of the dysregulation of vascular development that is characteristic of bronchopulmonary dysplasia.