OBJECTIVE: Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF.
RESULTS: ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy.
CONCLUSIONS: Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.

BACKGROUND: Cardiac remodeling is defined as cellular interstitial changes that lead dysfunction of the heart after injury. Placental growth factor (PlGF), a member of the VEGF family, has been reported to regulate cardiac hypertrophy in hemodynamic state. We therefore analyze the function of PlGF during cardiac remodeling using cardiac cells and fibroblasts, under Angiotensin II (AngII) stimulation.
METHODS: PlGF overexpressed mouse embryonic fibroblasts derived from C57BL/6 mice, were made by deficient retrovirus vector, designated as C57/PlGF. Only retrovirus vector introduced C57 cells (C57/EV) were used as control. After AngII stimulation, wound scratching assay and MTT proliferation assay with or without p38 MAPK inhibitor, SB205580 were performed in retrovirally-introduced C57 cells. Reactive oxygen species (ROS) production, NF-kB activation, IL-6 and TNF-α production were also measured. Then we assessed AngII-induced cell proliferation of mouse cardiac fibroblasts (CFs) and rat primary cardiomyocytes incubating with C57/PlGF conditioned-medium.
RESULTS: The PlGF production in C57/PlGF were confirmed by ELISA (1093.48 ± 3.5 pg/ml, ±SE). AngII-induced cell migration, proliferation and H2O2 production were increased in C57/PlGF compared with C57/EV. SB205580 inhibited the AngII-induced cell proliferation in C57/PlGF. In C57/PlGF cells, NF-kB activation was higher, followed by up-regulation of IL-6 and TNF-α production. CFs and cardiomyocytes proliferation increased when stimulated with C57/PlGF conditioned-medium.
CONCLUSIONS: The activation of fibroblast is stimulated by PlGF signaling via p38 MAPK/NF-kB pathway accompanied by elevation of ROS and inflammatory response. Furthermore, these signals stimulate the activation of CFs and cardiomyocytes, indicating that high circulating level of PlGF have a potential to regulate cardiac remodeling.

UNASSIGNED: Fetuses with growth abnormalities are at an increased risk of adverse neonatal outcomes. The aim of this study was to investigate if placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), or the sFlt-1/PlGF ratio were efficient predictive factors of adverse neonatal outcomes in small-for-gestational-age (SGA) newborns.
UNASSIGNED: A prospective observational multicenter cohort study was performed between 2020 and 2023. At the time of the SGA fetus diagnosis, serum angiogenic biomarker measurements were performed. The primary outcome was an adverse neonatal outcome, diagnosed in the case of any of the following: <34 weeks of gestation: mechanical ventilation, sepsis, necrotizing enterocolitis, intraventricular hemorrhage grade III or IV, and neonatal death before discharge; ≥34 weeks of gestation: Neonatal Intensive Care Unit hospitalization, mechanical ventilation, continuous positive airway pressure, sepsis, necrotizing enterocolitis, intraventricular hemorrhage grade III or IV, and neonatal death before discharge.
UNASSIGNED: In total, 192 women who delivered SGA newborns were included in the study. The serum concentrations of PlGF were lower, leading to a higher sFlt-1/PlGF ratio in the adverse outcome group. No significant differences in sFlt-1 levels were observed between the groups. Both PlGF and sFlt-1 had a moderate correlation with adverse neonatal outcomes (PlGF: R - 0.5, p < 0.001; sFlt-1: 0.5, p < 0.001). The sFlt-1/PlGF ratio showed a correlation of 0.6 (p < 0.001) with adverse outcomes. The uterine artery pulsatility index (PI) and the sFlt-1/PlGF ratio were identified as the only independent risk factors for adverse outcomes. An sFlt-1/PlGF ratio of 19.1 exhibited high sensitivity (85.1%) but low specificity (35.9%) in predicting adverse outcomes and had the strongest correlation with them. This ratio allowed the risk of adverse outcomes to be assessed as low with approximately 80% certainty.
UNASSIGNED: The sFlt-1/PlGF ratio seems to be an efficient predictive tool in adverse outcome risk assessment. More studies on large cohorts of SGA-complicated pregnancies with and without preeclampsia are needed to develop an optimal and detailed formula for the risk assessment of adverse outcomes in SGA newborns.

BACKGROUND: Preeclampsia is a significant cause of maternal and fetal morbidity and mortality, particularly in low- and middle-income countries like South Africa.
OBJECTIVE: The aim of our study was to investigate the association between placental growth factor (PlGF) and soluble FMS-like tyrosine kinase-1 (sFlt-1) in South African preeclamptic women of African ancestry, comorbid with HIV infection.
METHODS: The study population consisted of women attending a regional hospital in Durban, South Africa, stratified by pregnancy type (normotensive pregnant and preeclampsia) and HIV status. Preeclampsia was defined as new-onset hypertension and proteinuria. DNA was obtained from whole blood. The SNPs of interest were rs722503 in sFlt-1 and rs4903273 in PlGF.
RESULTS: Our findings suggest that single nucleotide polymorphisms of rs722503 analysis show no significant associations between the genotypic frequencies of rs722503 variants and preeclampsia risk in either HIV-negative or HIV-positive groups of women of African ancestry. Similarly, the rs493273 polymorphism showed no significant association with preeclampsia risk in either HIV-negative or HIV-positive pregnant women. Additionally, comparisons of dominant, recessive, and over-dominant allele models did not reveal significant associations. These findings suggest that these genetic variants may not significantly contribute to preeclampsia development in this African ancestry population. However, significant differences were observed in the rs4903273 genotype frequencies between normotensive and preeclamptic women, regardless of HIV status, over dominant alleles AA + GG vs AG showed a significant difference [OR = 2.706; 95% Cl (1.199-5.979); adjusted p = 0.0234*], also in normotensive compared to EOPE (OR = 2.804; 95% Cl (1.151-6.89) p = 0.0326* and LOPE (OR = 2.601; 95% Cl (1.0310-6.539) p = 0.0492*), suggesting that they may be the potential role of this variant in preeclampsia susceptibility.
CONCLUSIONS: The findings suggest that the rs722503 and rs493273 polymorphisms do not significantly contribute to preeclampsia susceptibility in HIV-negative or HIV-positive pregnant women. However, the rs4903273 genotype frequencies showed notable differences between normotensive and preeclamptic women, indicating a potential association with preeclampsia development in the African ancestry population irrespective of HIV status.

BACKGROUND: Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of placental protein and angiogenic factors are changed in SGA. Using data from a population-based pregnancy cohort, we estimated the relationships between levels of second-trimester pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF), and serum soluble fms-like tyrosine kinase-1 (sFlt-1) with SGA.
METHODS: Three thousand pregnant women were enrolled. Trained health workers prospectively collected data at home visits. Maternal blood samples were collected, serum aliquots were prepared and stored at -80℃. Included in the analysis were 1,718 women who delivered a singleton live birth baby and provided a blood sample at 24-28 weeks of gestation. We used Mann-Whitney U test to examine differences of the median biomarker concentrations between SGA (< 10th centile birthweight for gestational age) and appropriate-for-gestational-age (AGA). We created biomarker concentration quartiles and estimated the risk ratios (RRs) and 95% confidence intervals (CIs) for SGA by quartiles separately for each biomarker. A modified Poisson regression was used to determine the association of the placental biomarkers with SGA, adjusting for potential confounders.
RESULTS: The median PlGF level was lower in SGA pregnancies (934 pg/mL, IQR 613-1411 pg/mL) than in the AGA (1050 pg/mL, IQR 679-1642 pg/mL; p < 0.001). The median sFlt-1/PlGF ratio was higher in SGA pregnancies (2.00, IQR 1.18-3.24) compared to AGA pregnancies (1.77, IQR 1.06-2.90; p = 0.006). In multivariate regression analysis, women in the lowest quartile of PAPP-A showed 25% higher risk of SGA (95% CI 1.09-1.44; p = 0.002). For PlGF, SGA risk was higher in women in the lowest (aRR 1.40, 95% CI 1.21-1.62; p < 0.001) and 2nd quartiles (aRR 1.30, 95% CI 1.12-1.51; p = 0.001). Women in the highest and 3rd quartiles of sFlt-1 were at reduced risk of SGA delivery (aRR 0.80, 95% CI 0.70-0.92; p = 0.002, and aRR 0.86, 95% CI 0.75-0.98; p = 0.028, respectively). Women in the highest quartile of sFlt-1/PlGF ratio showed 18% higher risk of SGA delivery (95% CI 1.02-1.36; p = 0.025).
CONCLUSIONS: This study provides evidence that PAPP-A, PlGF, and sFlt-1/PlGF ratio measurements may be useful second-trimester biomarkers for SGA.

OBJECTIVE: To evaluate the correlation between maternal serum and urinary soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) levels and to assess their potential value in preeclampsia and fetal growth restriction.
METHODS: This case-control longitudinal prospective study was performed in 49 singleton pregnant women, divided into two clinical groups, low risk pregnancy (n = 23) and pregnancy complicated by preeclampsia (n = 26). Maternal serum and urinary sFlt-1 and PlGF levels were quantified by electrochemiluminescence. Every patient underwent an ultrasound for fetal biometry. Doppler assessment was done when estimated fetal weight was under the 10th centile. ROC curves were used to evaluate the predictive capability of serum and urinary angiogenic biomarkers and their ratios on preeclampsia. Linear regression was used to compare the values of serum and urinary sFlt-1 and PlGF and their ratios.
RESULTS: Urine biomarkers were positively associated with their serum values, being the best associated urinary PlGF (R2 = 0.73), which also showed the highest predictive capability of preeclampsia of urine biomarkers (AUC 0.866). The predictive capability of urinary sFlt-1 was much lower (AUC 0.640), but increased when adjusting by serum creatinine, a more precise parameter (AUC 0.863).
CONCLUSIONS: Urinary PlGF could be a lesser invasive alternative to circulating biomarkers to monitor pregnancies complicated with preeclampsia that need repeated controls of their pregnancy complication. Urinary sFlt-1 values need adjustment by serum creatinine to be reliable.

OBJECTIVE: To identify which components of maternal vascular malperfusion (MVM) pathology are associated with adverse pregnancy outcomes and to investigate the morphological phenotypes of MVM placental pathology and their relationship with distinct clinical presentations of pre-eclampsia and/or fetal growth restriction (FGR).
METHODS: Retrospective cohort study.
METHODS: Tertiary care hospital in Toronto, Canada.
METHODS: Pregnant individuals with low circulating maternal placental growth factor (PlGF) levels (<100 pg/mL) and placental pathology analysis between March 2017 and December 2019.
METHODS: Association between each pathological finding and the outcomes of interest were calculated using the chi-square test. Cluster analysis and logistic regression was used to identify phenotypic clusters, and their association with adverse pregnancy outcomes. Cluster analysis was performed using the K-modes unsupervised clustering algorithm.
METHODS: Preterm delivery <34+0 weeks of gestation, early onset pre-eclampsia with delivery <34+0 weeks of gestation, birthweight <10th percentile (small for gestational age, SGA) and stillbirth.
RESULTS: The diagnostic features of MVM most strongly associated with delivery <34+0 weeks of gestation were: infarction, accelerated villous maturation, distal villous hypoplasia and decidual vasculopathy. Two dominant phenotypic clusters of MVM pathology were identified. The largest cluster (n = 104) was characterised by both reduced placental mass and hypoxic ischaemic injury (infarction and accelerated villous maturation), and was associated with combined pre-eclampsia and SGA. The second dominant cluster (n = 59) was characterised by infarction and accelerated villous maturation alone, and was associated with pre-eclampsia and average birthweight for gestational age.
CONCLUSIONS: Patients with placental MVM disease are at high risk of pre-eclampsia and FGR, and distinct pathological findings correlate with different clinical phenotypes, suggestive of distinct subtypes of MVM disease.

BACKGROUND: Various immune mediators have a role in the progression of periodontitis. Placental Growth Factor (PLGF) is important during pregnancy and also is involved in the pathology of several diseases. Hence, this study aimed to evaluate salivary PLGF in health and periodontitis that seemingly has not been reported earlier.
METHODS: Fifty participants were grouped as healthy and periodontitis patients. Clinical history, periodontal parameters [Plaque Index (PI), Gingival Index (GI), probing pocket depth (PPD), clinical attachment loss (CAL), bleeding on probing (BoP)] were recorded; saliva was collected and PLGF was estimated using a commercially available ELISA kit. The data were statistically analyzed using Shapiro-Wilk\'s test, Kruskal-Wallis test, Dunn\'s post hoc test with Bonferroni correction, and Spearman\'s rank-order correlation coefficient. The significance level was set at p ≤ 0.05 for all tests.
RESULTS: Salivary PLGF levels comparison between the two groups showed no significant difference between both groups. Quantitatively, females had higher salivary PLGF levels than males. No significant association was observed between salivary PLGF levels and the severity of periodontitis. The periodontitis group showed statistically significant correlations between salivary PLGF levels, BoP(p = 0.005) and PPD(p = 0.005), and significant correlations of PLGF with PPD (p = 0.035) for both groups.
CONCLUSIONS: PLGF can be detected and measured in the saliva of healthy individuals and periodontitis patients. However, the role of PLGF in periodontal pathology needs to be further confirmed based on their salivary levels.

OBJECTIVE: To evaluate the performance of an artificial intelligence (AI) and machine learning (ML) model for first-trimester screening for pre-eclampsia in a large Asian population.
METHODS: This was a secondary analysis of a multicenter prospective cohort study in 10 935 participants with singleton pregnancies attending for routine pregnancy care at 11-13+6 weeks of gestation in seven regions in Asia between December 2016 and June 2018. We applied the AI+ML model for the first-trimester prediction of preterm pre-eclampsia (<37 weeks), term pre-eclampsia (≥37 weeks), and any pre-eclampsia, which was derived and tested in a cohort of pregnant participants in the UK (Model 1). This model comprises maternal factors with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor (PlGF). The model was further retrained with adjustments for analyzers used for biochemical testing (Model 2). Discrimination was assessed by area under the receiver operating characteristic curve (AUC). The Delong test was used to compare the AUC of Model 1, Model 2, and the Fetal Medicine Foundation (FMF) competing risk model.
RESULTS: The predictive performance of Model 1 was significantly lower than that of the FMF competing risk model in the prediction of preterm pre-eclampsia (0.82, 95% confidence interval [CI] 0.77-0.87 vs. 0.86, 95% CI 0.811-0.91, P = 0.019), term pre-eclampsia (0.75, 95% CI 0.71-0.80 vs. 0.79, 95% CI 0.75-0.83, P = 0.006), and any pre-eclampsia (0.78, 95% CI 0.74-0.81 vs. 0.82, 95% CI 0.79-0.84, P < 0.001). Following the retraining of the data with adjustments for the PlGF analyzers, the performance of Model 2 for predicting preterm pre-eclampsia, term pre-eclampsia, and any pre-eclampsia was improved with the AUC values increased to 0.84 (95% CI 0.80-0.89), 0.77 (95% CI 0.73-0.81), and 0.80 (95% CI 0.76-0.83), respectively. There were no differences in AUCs between Model 2 and the FMF competing risk model in the prediction of preterm pre-eclampsia (P = 0.135) and term pre-eclampsia (P = 0.084). However, Model 2 was inferior to the FMF competing risk model in predicting any pre-eclampsia (P = 0.024).
CONCLUSIONS: This study has demonstrated that following adjustment for the biochemical marker analyzers, the predictive performance of the AI+ML prediction model for pre-eclampsia in the first trimester was comparable to that of the FMF competing risk model in an Asian population.

BACKGROUND: Preeclampsia is characterized by maternal endothelial activation and placental dysfunction. Imbalance in maternal angiogenic and vasoactive factors has been linked to the pathophysiology. The contribution of the placenta as a source of these factors remains unclear. Furthermore, little is known about fetal angiogenic and vasoactive proteins and the relation between maternal and fetal levels.
OBJECTIVE: We describe placental growth factor, soluble Fms-like tyrosine kinase 1, soluble endoglin, and endothelin 1-3 in 5 vessels in healthy pregnancies, early- and late-onset preeclampsia. Specifically, we aimed to (1) compare protein abundance in vessels at the maternal-fetal interface between early- and late-onset preeclampsia, and healthy pregnancies, (2) describe placental uptake and release of proteins, and (3) describe protein abundance in the maternal vs fetal circulations.
METHODS: Samples were collected from the maternal radial artery, uterine vein and antecubital vein, and fetal umbilical vein and artery in 75 healthy and 37 preeclamptic mother-fetus pairs (including 19 early-onset preeclampsia and 18 late-onset preeclampsia), during scheduled cesarean delivery. This method allows estimation of placental release and uptake of proteins by calculation of venoarterial differences on each side of the placenta. The microarray-based SomaScan assay quantified the proteins.
RESULTS: The abundance of soluble Fms-like tyrosine kinase 1 and endothelin 1 was higher in the maternal vessels in preeclampsia than in healthy pregnancies, with the highest abundance in early-onset preeclampsia. Placental growth factor was lower in the maternal vessels in early-onset preeclampsia than in both healthy and late-onset preeclampsia. Maternal endothelin 2 was higher in preeclampsia, with late-onset preeclampsia having the highest abundance. Our model confirmed placental release of placental growth factor and soluble Fms-like tyrosine kinase 1 to the maternal circulation in all groups. The placenta released soluble Fms-like tyrosine kinase 1 into the fetal circulation in healthy and late-onset preeclampsia pregnancies. Fetal endothelin 1 and soluble Fms-like tyrosine kinase 1 were higher in early-onset preeclampsia, whereas soluble endoglin and endothelin 3 were lower in both preeclampsia groups than healthy controls. Across groups, abundances of placental growth factor, soluble Fms-like tyrosine kinase 1, and endothelin 3 were higher in the maternal artery than the fetal umbilical vein, whereas endothelin 2 was lower.
CONCLUSIONS: An increasing abundance of maternal soluble Fms-like tyrosine kinase 1 and endothelin 1 across the groups healthy, late-onset preeclampsia and early-onset combined with a positive correlation may suggest that these proteins are associated with the pathophysiology and severity of the disease. Elevated endothelin 1 in the fetal circulation in early-onset preeclampsia represents a novel finding. The long-term effects of altered protein abundance in preeclampsia on fetal development and health remain unknown. Further investigation of these proteins\' involvement in the pathophysiology and as treatment targets is warranted.