Growth Factor In Pre-eclampsia Research Articles

Clinical Analysis of Serum Soluble Tyrosine Kinase Receptor-1 and Placental Growth Factor in Pre-eclampsia

Objective: To study the clinical application effect of using serum soluble tyrosine kinase receptor-1 (sFlt-1) and placental growth factor (PlGF) in pre-eclampsia. Methods: From September 2021 to September 2023, 58 cases of pre-eclampsia patients who underwent physical examination during pregnancy and eventually gave birth in Xinghua People’s Hospital were the observation group of this study and 795 cases of healthy pregnant women who underwent pregnancy examination in this hospital during the same period of time were the control group of this study; 38 cases of mild pre-eclampsia in the observation group were treated as the mild group and 20 cases of severe pre-eclampsia patients were treated as the severe group and the serum sFlt-1 and PlGF were used to compare the results of the observation group and the control group. Compare the serum sFlt-1 and PlGF levels between the observation and control groups; compare the serum sFlt-1 and PlGF levels between the mild and severe groups. Results: The serum PlGF level of the observation group was lower than that of the control group, and the sFlt-1 level was higher than that of the control group, P < 0.05; the serum PlGF level of the mild group was higher than that of the severe group, and the sFlt-1 level was lower than that of the control group, P < 0.05; the results showed that the serum and urine sFlt-1 and PlGF levels of pregnant women of all the three groups were elevated with the aggravation of the condition of pre-eclampsia, and the sFlt-1/PlGF ratio also increased. The differences of sFlt-1/PlGF in serum and urine of the three groups were compared, with P < 0.05; the above ratios of the patients in the mild group were higher than those of the control group and those of the severe group were higher than those of the mild group, with P < 0.05. Conclusion: Serum sFlt-1 level was high in preeclamptic patients, while serum PlGF was low in preeclamptic patients.

Identification of vascular endothelial growth factor in preeclampsia in Iraqi women.

Preeclampsia (PE) is a major obstetric syndrome and represents a pregnancy hypertensive disease affecting about 2-8% of pregnancies. Typically, it occurs after 20 weeks of pregnancy, being classified as early or late in accordance with the gestational age at diagnosis or delivery. An imbalance between angiogenic and antiangiogenic factors has an important role in the pathophysiology of PE. It was hypothesized that the dysfunctional endothelium contributes to the pathogenesis of PE. A change in the production of Vascular endothelial growth factor (VEGR), a biomarker of endothelial dysfunction, is associated with this disease, whether presenting an increase, decrease, or being at a normal level. This study examined the associations between VEGF and preeclampsia and the importance of this VEGF as a predictor of its severity. This case-control study included 50 patients with preeclampsia and 50 normotensive pregnant women in the control group. Venous blood was aspirated from each patient, and VEGF levels were measured from sera. The mean VEGF for patients with mild PE was 29.410±18.976 pg/ml, for those with severe PE it was 36.188±36.98 pg/ml, and for normotensive women it was 92.104±154.715 pg/ml. There were significant differences in VEGF levels between the studied groups (P=0.024). This study showed that serum VEGF levels were significantly reduced in patients with preeclampsia compared with normotensive pregnant women, suggesting marked endothelial dysfunction. This led to widespread vasoconstriction and, in turn, caused hypertension and proteinuria.

Placental growth factor in suspected preterm pre-eclampsia: a review of the evidence and practicalities of implementation.

Despite extensive research, the pathophysiology and prevention of pre-eclampsia remain elusive, diagnosis is challenging, and pre-eclampsia remains associated with adverse maternal and perinatal outcomes. Angiogenic biomarkers, including placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), have been identified as valuable biomarkers for preterm pre-eclampsia, accelerating diagnosis and reducing maternal adverse outcomes by risk stratification, with enhanced surveillance for high-risk women. PlGF-based testing is increasingly being implemented in clinical practice in several countries. This review provides healthcare providers with an understanding of the evidence for PlGF-based testing and describes the practicalities and challenges to implementation. TWEETABLE ABSTRACT: Placental growth factor in pre-eclampsia: evidence and implementation of testing.

Urinary placental growth factor in preeclampsia and fetal growth restriction: An alternative to circulating biomarkers?

To correlate plasma and urinary soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PIGF) in preeclampsia (PE) and fetal growth restriction (FGR) and assess the performance in detecting established disease. A cross-sectional case-control study recruited 26-40 weeks gestation pregnancies into four clinical groups: normal pregnancy, PE, PE + FGR, and FGR. enzyme-linked immunosorbent assay (ELISA) measurements of urinary and plasma sFlt-1 and PlGF levels were performed. Urinary levels of sFlt-1 and PIGF were normalized to creatinine. Spearman's rank correlation was used to assess the association between plasma and urinary levels of sFlt-1 and PIGF, and receiver operating characteristic graphs were used to quantify the performance of each individual marker and their ratios in predicting normal versus pathological pregnancies affected by preeclampsia and/or FGR. There was a significant correlation between plasma PlGF and urinary PlGF (r = 0.718, P < 0.001) in all groups. In the pathological groups, plasma sFlt-1 and urinary sFlt-1 as well as plasma sFlt-1: PIGF ratio and urinary sFlt-1: PlGF ratio were higher, but plasma PIGF and urinary PlGF were lower when compared to normal pregnancy. Plasma PIGF and plasma sFlt-1: PlGF ratio was comparable in performance to urinary PlGF and urinary sFlt-1: PIGF ratio for the diagnosis of preeclampsia and/or FGR. Urinary PIGF can be used as an alternative to circulating biomarkers in preeclampsia and FGR. Plasma sFlt-1, PlGF and sFlt-1: PlGF ratio as well as urinary PIGF and sFlt-1: PlGF ratio can be used to differentiate between normal pregnancy and pregnancies complicated by preeclampsia and FGR.

Placental growth factor in pre-eclampsia: friend or foe?

Preeclampsia is a hypertensive disorder of pregnancy that can present with proteinuria or end-organ damage. Preeclampsia occurs in approximately 5% of pregnancies and is associated with significant fetal and maternal morbidity that can extend beyond the period of pregnancy. The exact pathogenesis of preeclampsia is still unclear; however, evidence supports a role for placental ischemia and disordered development and remodeling of the placental vasculature.1 These processes are especially relevant in “placental” or “early” preeclampsia, in which they are thought to contribute to an altered repertoire of placenta-derived factors that promote maternal endothelial dysfunction.

The relationship between circulating tissue transglutaminase, soluble fms-like tyrosine kinase-1, soluble endoglin and vascular endothelial growth factor in pre-eclampsia.

Preeclampsia (PE) is a pregnancy-specific syndrome that causes substantial maternal and fetal morbidity and mortality. Increased production of antiangiogenic factors, soluble fms-like tyrosine kinase receptor-1 (sFlt-1) and soluble endoglin (sEng), as well as decreased circulating levels of free vascular endothelial growth factor (VEGF), contribute to the pathophysiology of PE. Our objective was to evaluate a novel placenta-related factor, tissue transglutaminase (tTG), in PE and to investigate the correlation among tTG and sFlt-1, sEng and VEGF levels in both normotensive pregnant patients and PE patients. A total of 205 pregnant primigravid women were recruited and divided into a normotensive group (n=100), a mild PE group (n=45) and a severe PE group (n=60). Circulating serum tTG, sFlt-1, sEng and free VEGF levels were determined using an enzyme-linked immunosorbent assay. The severe PE group showed higher levels of tTG, sFlt-1 and sEng than the mild PE and normotensive groups. Free VEGF levels were lower in the severe PE group than in the mild PE and normotensive groups. tTG correlated significantly with sFlt-1, sEng and VEGF in the PE groups, whereas this correlation was not observed in the normotensive group. The tTG, sFlt-1, sEng and VEGF levels showed a significant correlation with mean arterial pressure in the PE groups but not in the normotensive group. The tTG, sFlt-1, sEng and VEGF levels correlated with the degree of proteinuria. Our results reveal that tTG is associated with sFlt-1, sEng and VEGF in the maternal circulation of PE patients, suggesting that tTG may have a role in the pathogenesis of PE.

Placental growth factor administration prevents hypertension, increased sFlt‐1 levels and reduced glomerular filtration rate responses to placental ischemia

Preeclampsia is a pregnancy‐specific disorder noted by new‐onset hypertension in the mother accompanied by a variety of other cardiovascular disturbances. Unfortunately, the most effective treatment is early delivery of the fetus and the ischemic placenta. Progress toward treatment has found that placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in human patients stimulates release of hypertensive placental factors into the maternal circulation. The anti‐angiogenic factor sFlt‐1, which antagonizes and reduces bioavailable vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is elevated in RUPP rats and preeclamptic patients. Although PlGF and VEGF are both natural ligands for sFlt‐1, VEGF also binds with high‐affinity to Flk1 (VEGFR2) causing side‐effects related to excess Flk1 signaling including edema. In contrast, PlGF is specific for sFlt‐1. Thus, we tested the hypothesis that PlGF treatment would reduce placental ischemia‐induced hypertension without any adverse consequences to the mother or fetus. On gestational day 14, Sprague Dawley rats were randomized in to three groups: normal pregnant (NP, N=9), RUPP (N=11) and RUPP + 180 μg/kg/day PlGF (N=6). The rhPlGF (AG31, a purified‐recombinant human PlGF) was infused via intraperitoneal osmotic minipump. Mean arterial blood pressure (MAP, carotid catheter); glomerular filtration rate (GFR); placental and fetal weights; and plasma sFlt‐1 levels were assessed on day 19. Data is mean ± standard error. MAP (NP: 104±1 vs. RUPP: 123±4 mmHg) and plasma sFlt‐1 levels (NP: 26±12 vs. RUPP: 660±150 ng/mL) were significantly higher (P&lt;0.05) in the RUPP rats. Whereas, total placental weights (NP: 6.1±0.6 vs. RUPP: 2.1±0.3 g); total fetal weights (NP: 26.1±2.5 vs. RUPP: 9.2±1.3 g); and GFR (NP: 4.2±0.4 vs. RUPP: 3.8±0.3 mL/min) were significantly reduced (P&lt;0.05) in the RUPP rats. Treatment of RUPP rats with rhPlGF significantly reduced (P&lt;0.05) MAP (105±3 mmHg) and sFlt‐1 levels (79±17 ng/mL); did not alter placental weights (2.6±0.5 g) or fetal weights (12.6±2.3 g); but significantly elevated (P&lt;0.05) GFR (3.0±0.1) compared to untreated RUPP rats. There were no major adverse maternal consequences such as signs of edema with rhPlGF. These data indicate that the increased sFlt‐1 and reduced PlGF known to occur as a result of placental ischemia contribute to the development of maternal hypertension. In conclusion, our finding that rhPlGF prevents placental ischemia‐induced hypertension and restores renal hemodynamics suggests a strong therapeutic potential for this growth factor in preeclampsia by interfering in anti‐angiogenic pathways.Support or Funding InformationSBIR 1R43HD082657, T32HL105324‐01, P01HL051971

Clinical Implications

Clinical Implications

Abstract 038: Placental Growth Factor Supplementation Abolishes Placental Ischemia-induced Hypertension

Preeclampsia (PE) is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Progress toward potential therapeutic targets has found that placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in human patients stimulates the release of hypertensive placental factors into the maternal circulation. For example, the antiangiogenic factor sFlt-1, which antagonizes and reduces bioavailable vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is significantly elevated in PE patients and RUPP rats. It is clear that reductions in VEGF promote hypertension in RUPP rats as supplementation with recombinant VEGF at 180 ug/kg/day abolished the hypertension. However, it is unknown if reductions in PlGF levels also contribute to the hypertensive response. Thus, we tested the hypothesis that PlGF treatment would reduce placental ischemia-induced hypertension. On gestational day 14, Sprague Dawley rats were randomized to three groups: normal pregnant (NP, N=6), RUPP (N=5) and RUPP + 180 ug/kg/day PlGF (N=7). The rPlGF (AG31, a purified-recombinant human PlGF) was infused via i.p. osmotic minipump. Mean arterial blood pressure (MAP, carotid catheter) and pregnancy weights were assessed on day 19. MAP was significantly higher in RUPP than NP rats (123±4 vs. 104±1, P&lt;0.05). PlGF reversed these levels to NP values (105±3, P&lt;0.05 vs. RUPP). Placental weights (NP: 0.5±0.02; RUPP: 0.51±0.04; and RUPP+rPlGF: 0.5±0.05) and fetal weights (NP: 2.30±0.07; RUPP: 2.00±0.15; and RUPP+rPlGF: 2.09±0.07) were similar among all groups. The number of live fetuses was reduced in RUPP than NP rats (5±2 vs. 12±1, P&lt;0.05) with a slight increase in the RUPP+rPlGF group (8±1). The number of fetal absorptions was increased in RUPP than NP rats (9±2 vs. 2±1, P&lt;0.05) with a slight increase in the RUPP+rPlGF group (5±1). In conclusion, these data indicate that the reductions in PlGF that occur as a result of placental ischemia contribute to the development of maternal hypertension. Our novel finding that rPlGF abolishes placental ischemia-induced hypertension suggests a strong role and therapeutic potential for this growth factor in PE.

Impaired proliferation of pancreatic beta cells, by reduced placental growth factor in pre-eclampsia, as a cause for gestational diabetes mellitus.

Reduced increase in serum placental growth factor (PLGF) levels frequently occurs in patients with pre-eclampsia (PE) and thus has been used as a predictive factor for developing PE. However, it has remained elusive how shortage of PLGF could affect pancreatic endocrine homoeostasis and function in pregnancy to lead to development of gestational diabetes mellitus (GDM). We used l-NAME injection in mice, as a model of human PE, in which PLGF levels were significantly reduced. We not only confirmed reduced serum PLGF levels in patients with PE but also detected strong correlation of serum PLGF levels and presence of GDM. We found that growth of beta cell mass during pregnancy was significantly impaired by l-NAME injection, as a result of reduced beta cell proliferation. This may explain the higher risk of developing GDM in patients with PE. Moreover, provision of exogenous PLGF in l-NAME-treated pregnant mice significantly rescued beta cell proliferation, with subsequent increase in beta cell mass, suggesting that shortage in PLGF may be responsible for impaired beta cell growth and higher occurrence of GDM in patients with PE. Our study highlighted a pivotal role for PLGF in prevention and treatment of GDM in patients with PE.

Examining the correlation between placental and serum placenta growth factor in preeclampsia

Decreased levels of serum placenta growth factor (PlGF) are associated with preeclampsia. We sought to determine whether serum and placental levels of PlGF (sPlGF and pPlGF) are associated with preeclampsia and whether there is a correlation between serum and placental PlGF levels. These analyses were part of a larger, prospective, case-control study. Cases were women with preeclampsia. Controls were women without preeclampsia who delivered at term. Analyses included nonparametric tests to compare medians, logistic regression to estimate odds, and calculation of correlation coefficients. Twenty-four cases (10 preterm, 14 term) were compared with 14 controls. Median levels of PlGF were significantly lower in cases than controls (pPlGF: 232.6 vs 363.4 pg/mL, P = .02; sPlGF: 85.5 vs 274.4 pg/mL, P < .001). Serum and placental PlGF were correlated (overall: 39%, P = .006; cases with preterm preeclampsia and growth restriction: 87%, P = .02). Serum and placental PlGF are independently associated with preeclampsia and correlated with each other.

Vascular endothelial growth factor expression is unaltered in placentae and myometrial resistance arteries from pre‐eclamptic patients

The purpose of this study is to determine whether there is any difference for vascular endothelial growth factor expression in placentae and myometrial resistance arteries from control and pre-eclamptic patients to clarify the source of the increased total vascular endothelial growth factor in pre-eclampsia. With placentae tissue samples and small pieces of myometrium from the controls (n=10) and pre-eclampsia patients (n=7), vascular endothelial growth factor immunohistochemistry and mRNA in situ hybridization were performed. We also measured the serum vascular endothelial growth factor levels by competitive enzyme immunoassay at the same time. Vascular endothelial growth factor was identified primarily in syncytiotrophoblast in placental tissue, and it was also identified in smooth muscle cells in the myometrium and perivascular smooth muscle in myometrial resistance arteries. However, there were no differences in vascular endothelial growth factor expression between the groups in the presence of elevated serum levels of total vascular endothelial growth factor in pre-eclamptic patients (median 18.2 ng/ml versus 4.9 ng/ml). This study suggests that the placenta and perivascular smooth muscle are not the origin of the increased total vascular endothelial growth factor in pre-eclampsia. To clearly understand the role of vascular endothelial growth factor in pre-eclampsia, further studies are required to determine the sites of increased vascular endothelial growth factor synthesis.

Decreased maternal serum placenta growth factor in early second trimester and preeclampsia

Objective: To compare early second-trimester maternal serum placenta growth factor concentrations in patients with subsequent development of preeclampsia and those with normal pregnancies. Methods: We conducted a case-control analysis of stored maternal serum of 27 women who subsequently developed preeclampsia and 227 randomly selected normal controls during the gestational period of 14–19 weeks. Using such a sample size, there was a greater than 95% power to test a difference in the primary study interest. A quantitative sandwich enzyme immunoassay was used to measure the maternal serum placenta growth factor concentration. For statistical analysis, Mann–Whitney U tests, multiple linear regression analysis, multivariable logistic regression model, and receiver-operating characteristic (ROC) curve were used. P < .05 was considered statistically significant. Results: Maternal serum placenta growth factor concentration was associated with the occurrence of subsequent preeclampsia ( P < .001) and gestational age ( P < .001). The median (interquartile range) of multiples (MoM) of the gestational age stratified median for placenta growth factor in preeclampsia was 0.55 (0.33, 0.85). The ROC curve revealed that the specificity was 70% when the diagnostic sensitivity was 70%, and the optimal cutoff value of placenta growth factor MoM was 0.76. The risk of developing preeclampsia subsequently was increased 2.5-fold for maternal serum placenta growth factor concentration decrements of 0.1 MoM. Conclusion: A decreased maternal serum placenta growth factor concentration in the early second trimester is highly associated with the subsequent development of preeclampsia, but a large prospective study is needed to explore its use as an early predictor for the condition.

Increased Circulating Levels of Vascular Endothelial Growth Factor in Preeclampsia

Objective: To determine whether levels of vascular endothelial growth factor (VEGF) are raised in pregnancies complicated by preeclampsia.Methods: Samples of serum were collected from 10 patients with preeclampsia and 10 gestation-matched normotensive controls. Levels of VEGF were measured in samples using a radioimmunoassay with a polyclonal antibody capable of recognizing all VEGF isoforms.Results: Vascular endothelial growth factor was detectable in all samples assayed. The median serum concentration of VEGF in the preeclamptic subjects was 5.1 μg/L (interquartile range: 4.7-5.5 μg/L) and for the control group 3.9 μg/L (interquartile range: 3.4-4.1 μg/L). Serum VEGF levels were significantly higher (p < 0.001, Mann-Whitney U-test) in the preeclamptic subjects.Conclusion: The raised circulating levels of VEGF in preeclampsia and the known effects of this growth factor on endothelial cell function suggest that VEGF may be involved in the pathophysiology of this disease.