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Introduction To assess the rate of change in soluble fms‐like tyrosine kinase‐1/placental growth factor (sFlt‐1/PlGF) ratio and PlGF levels per week compared to a single sFlt‐1/PlGF ratio or PlGF level to predict preterm birth for pregnancies complicated by fetal growth restriction. Material and methods A prospective cohort study of pregnancies complicated by isolated fetal growth restriction. Maternal serum PlGF levels and the sFlt‐1/PlGF ratio were measured at 4‐weekly intervals from recruitment to delivery. We investigated the utility of PlGF levels, sFlt‐1/PlGF ratio, change in PlGF levels per week or sFlt‐1/PlGF ratio per week. Cox‐proportional hazard models and Harrell's C concordance statistic were used to evaluate the effect of biomarkers on time to preterm birth. Results The total study cohort was 158 pregnancies comprising 91 (57.6%) with fetal growth restriction and 67 (42.4%) with appropriate for gestational age controls. In the fetal growth restriction cohort, sFlt‐1/PlGF ratio and PlGF levels significantly affected time to preterm birth (Harrell's C: 0.85–0.76). The rate of increase per week of the sFlt‐1/PlGF ratio (hazard ratio [HR] 3.91, 95% confidence interval [CI]: 1.39–10.99, p = 0.01, Harrell's C: 0.74) was positively associated with preterm birth but change in PlGF levels per week was not (HR 0.65, 95% CI: 0.25–1.67, p = 0.37, Harrell's C: 0.68). Conclusions Both a high sFlt‐1/PlGF ratio and low PlGF levels are predictive of preterm birth in women with fetal growth restriction. Although the rate of increase of the sFlt‐1/PlGF ratio predicts preterm birth, it is not superior to either a single elevated sFlt‐1/PlGF ratio or low PlGF level. A single absolute high sFlt‐1/PlGF ratio or low PlGF level is sufficient to reliably predict PTB in women with FGR. The change in the sFlt‐1/PlGF ratio is not superior to either a single elevated sFlt‐1/PlGF ratio or low PlGF level.

The purpose of this study was to evaluate serum levels of anti- and pro-angiogenic substances measured using enzyme-linked immunosorbent assays and their ratios in pregnancies complicated by different clinical subsets of placental ischemic syndrome: preeclampsia and/or fetal growth restriction. A prospective case-control study was performed consisting of 77 singleton pregnancies complicated by preeclampsia, preeclampsia with concurrent fetal growth restriction (FGR), and isolated normotensive FGR pairwise matched by gestational age with healthy pregnancies. The entire study cohort was analyzed with respect to adverse pregnancy outcomes that occurred. In all investigated subgroups, placental growth factor (PlGF) was lower and soluble endoglin (sEng), the soluble fms-like tyrosine kinase-1—sFlt-1/PlGF and sFlt-1*sEng/PlGF ratios were higher than in the control group. The differences were most strongly pronounced in the PE with concurrent FGR group and in the sFlt-1/PlGF ratio. The highest sFlt-1 values in preeclamptic patients suggest that this substance may be responsible for reaching the threshold needed for PE to develop as a maternal manifestation of ischemic placental disease. The FGR is characterized by an elevated maternal sFlt-1/PlGF ratio, which boosts at the moment of indicated delivery due to fetal risk. We concluded that angiogenic imbalance is reflective of placental disease regardless of its clinical manifestation in the mother, and may be used as support for the diagnosis and prognosis of FGR.

The vascular endothelial growth factor (VEGF) family members, VEGF-A, placenta growth factor (PlGF), and to a lesser extent VEGF-B, play an essential role in tumor-associated angiogenesis, tissue infiltration, and metastasis formation. Although VEGF-A can activate both VEGFR-1 and VEGFR-2 membrane receptors, PlGF and VEGF-B exclusively interact with VEGFR-1. Differently from VEGFR-2, which is involved both in physiological and pathological angiogenesis, in the adult VEGFR-1 is required only for pathological angiogenesis. Besides this role in tumor endothelium, ligand-mediated stimulation of VEGFR-1 expressed in tumor cells may directly induce cell chemotaxis and extracellular matrix invasion. Furthermore, VEGFR-1 activation in myeloid progenitors and tumor-associated macrophages favors cancer immune escape through the release of immunosuppressive cytokines. These properties have prompted a number of preclinical and clinical studies to analyze VEGFR-1 involvement in the metastatic process. The aim of the present review is to highlight the contribution of VEGFs/VEGFR-1 signaling in the progression of different tumor types and to provide an overview of the therapeutic approaches targeting VEGFR-1 currently under investigation.

Gestational diabetes mellitus (GDM) affects approximately 14% of pregnancies globally, with rising incidence depending on the diagnostic criteria used. In the UK, screening relies on risk factors at booking, followed by a diagnosis via an oral glucose tolerance test in the second trimester. This approach may lack sensitivity and has poor tolerability. Emerging evidence suggests that GDM pathophysiology begins in the first trimester, with biomarkers showing potential for early prediction. Identifying these could enable earlier risk stratification, improved diagnostic pathways, and better maternal–fetal outcomes. This scoping review maps the existing literature on first‐trimester biomarkers of GDM to evaluate their clinical utility and integration into predictive models. A literature search was conducted using Medline, Embase, and PubMed to identify studies on first‐trimester biomarkers of GDM. Inclusion criteria included (1) studies investigating biomarkers at <15 weeks' gestation; (2) studies that diagnosed GDM using an OGTT with recognized diagnostic guidelines or clearly stated glucose thresholds. A total of 133 studies were included, reporting a wide range of biomarkers (145 in total). PAPP‐A was generally lower in GDM, with mixed findings for β‐hCG and PlGF. Metabolic markers, including lipid profiles, fasting glucose, and HbA1c, were often elevated. Inflammatory markers, such as WCC, neutrophils, and CRP, were higher in those later diagnosed with GDM. First‐trimester biomarkers highlight GDM's complex pathophysiology. PAPP‐A shows predictive potential, while metabolic and inflammatory biomarkers suggest early systemic dysfunction. Emerging tools like 3D ultrasonography indicate placental structural changes. Larger studies are needed to validate these biomarkers and integrate them into predictive models to improve maternal–fetal outcomes. Of the 145 first‐trimester biomarkers identified for gestational diabetes mellitus, many show potential for early prediction. This highlights a window for intervention before the current clinical standards of diagnosis in the second trimester.

About 26% of all pregnancies result in miscarriage, with up to 10% occurring in clinically diagnosed pregnancies. Additionally, recurrent pregnancy loss affects approximately 5% of couples of childbearing age. Although there are several known causes of pregnancy loss in the first half, including parental chromosomal abnormalities, uterine malformations the possible role of placental growth factor (PLGF) remains unclear. The aim of this study was to evaluate the possible predictive role of serum and urinary PLGF for miscarriages in the first trimester of pregnancy. Case-control studies were conducted. The study included 347 pregnant women, the group of miscarriages comprised 156 and the control group 191. The study did not include patients with serious health problems or high risk of miscarriage. Miscarriages were identified: confirmed clinical and ultrasound signs of embryo/fetal expulsion, anembryonic pregnancy and missed abortion. Concentrations of serum and urinary PLGF were detected by ELISA. Serum PLGF concentrations in miscarriage were 19.8 (12.7-31.9) pg/mL, which was significantly lower than serum PLGF concentrations in uncomplicated pregnancy of 45.5 (25.4-60.0) pg/mL p <0.0001. ROC analysis revealed the diagnostic significance of serum PLGF: AUC 0.765 (CI 0.717-0.809) (p <0.0001), Se 84.6% (CI 77.7-90.0) Sp 68.7% (61.7-75.1), with cut-off ≤35.6 pg/mL, diagnostic odds ratio (DOR) 12. Odds ratio for miscarriages for serum PLGF concentration <35.6 pg/mL was 10.9 (6.5-18.4). Evaluation of urinary PLGF did not reveal diagnostic and prognostic efficacy of miscarriages. The serum PLGF might be considered as a prediction marker of the miscarriages with a suggested cut off concentration of 35.6 pg/mL. A further investigation should be carried out on the larger cohorts from various geographical areas.

Preeclampsia (PE) occurs in approximately 2–8% of all pregnancies worldwide and represents one of the primary causes of maternal and fetal morbidity and mortality. Angiogenic growth factors such as placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), along with their tyrosine kinase receptor (Flt-1), play a central role in placental and fetal development. Impaired placentation results in the excessive release of the antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) which is pivotal in the pathogenesis of PE. By binding to and neutralizing angiogenic factors, sFlt-1 disrupts normal angiogenic signaling, creating an imbalance that is often detectable before clinical symptoms of PE appear. Recent studies have highlighted the prognostic potential of the sFlt-1/PlGf ratio as an early indicator of PE risk, since this ratio has demonstrated value in both confirming and excluding PE in the high-risk population. Its incorporation into routine medical care has the potential to reduce unnecessary hospital admissions, intensive management, and premature deliveries, ultimately lowering healthcare costs. The objective of this review is to highlight the clinical utility of the sFlt-1/PlGf ratio in the prediction, diagnosis, and management of preeclampsia and to emphasize the cost-effectiveness of implementing sFlt-1/PlGF ratio measurement in the care of women at risk of developing PE.

Preeclampsia is a multisystem, multiorgan hypertensive disorder of pregnancy responsible for maternal and perinatal morbidity and mortality in low- and middle-income countries. The classic diagnostic features hold less specificity for preeclampsia and its associated adverse outcomes, suggesting a need for specific and reliable biomarkers for the early prediction of preeclampsia. The imbalance of pro- and antiangiogenic circulatory factors contributes to the pathophysiology of preeclampsia. Several studies have examined the profile of angiogenic factors in preeclampsia to search for a biomarker that will improve the diagnostic ability of preeclampsia and associated adverse outcomes. This may help in more efficient patient management and the reduction of associated health care costs. This article reviews the findings from previous studies published to date on angiogenic factors and suggests a need to apply a multivariable model from the beginning of pregnancy and continuing throughout gestation for the early and specific prediction of preeclampsia.

Objective Macrophages show extreme heterogeneity and different subsets have been characterized by their activation route and their function. For instance, macrophage subsets are distinct by acting differently under pathophysiological conditions such as inflammation and cancer. Macrophages also contribute to angiogenesis, but the role of various specific subsets in angiogenesis has not been thoroughly investigated. Methods and results Matrigel supplemented with macrophage subsets [induced by IFNγ (M1), IL-4 (M2a) or IL-10 (M2c)] was injected subcutaneously in C57BL/6 J mice and analyzed by CD31 staining after 14 days. Increased numbers of endothelial cells and tubular structures were observed in M2-enriched plugs compared to control and other subsets. Additionally, more tubular structures formed in vitro in the presence of M2 macrophages or their conditioned medium. To identify a mechanism for the pro-angiogenic effect, gene expression of angiogenic growth factors was analyzed. Induced expression of basic fibroblast growth factor ( Fgf2 ), insulin-like growth factor-1 ( Igf1 ), chemokine (C–C motif) ligand 2 ( Ccl2 ) and placental growth factor ( Pgf ) was observed in M2 macrophages. Using a blocking antibody of PlGF to inhibit M2c induced angiogenesis resulted in mildly reduced (40 %) tube formation whereas neutralization of FGF-2 (M2a) signaling by sFGFR1-IIIc affected tube formation by nearly 75 %. Conclusions These results indicate that macrophages polarized towards an M2 phenotype have a higher angiogenic potential compared to other subsets. Furthermore, we propose FGF signaling for M2a- and PlGF signaling for M2c-induced angiogenesis as possible working mechanisms, yet, further research should elucidate the exact mechanism for M2-induced angiogenesis.

The sharing of molecules function that affects both tumor growth and neoangiogenesis with cells of the immune system creates a mutual interplay that impairs the host’s immune response against tumor progression. Increasing evidence shows that tumors are able to create an immunosuppressive microenvironment by recruiting specific immune cells. Moreover, molecules produced by tumor and inflammatory cells in the tumor microenvironment create an immunosuppressive milieu able to inhibit the development of an efficient immune response against cancer cells and thus fostering tumor growth and progression. In addition, the immunoediting could select cancer cells that are less immunogenic or more resistant to lysis. In this review, we summarize recent findings regarding the immunomodulatory effects and cancer progression of the angiogenic growth factor namely placental growth factor (PlGF) and address the biological complex effects of this cytokine. Different pathways of the innate and adaptive immune response in which, directly or indirectly, PlGF is involved in promoting tumor immune escape and metastasis will be described. PlGF is important for building up vascular structures and functions. Although PlGF effects on vascular and tumor growth have been widely summarized, its functions in modulating the immune intra-tumoral microenvironment have been less highlighted. In agreement with PlGF functions, different antitumor strategies can be envisioned.