PlGF/FLT-1 deficiency leads to reduced STAT3-C/EBPß signaling and aberrant polarization in decidual macrophages during early spontaneous abortion.

Introduction: Dysregulated macrophage polarization (excessive M1-like or limited M2-like macrophages) in the early decidua contributes to allogeneic fetal rejection and thus early spontaneous abortion. However, the modulators of M1/M2 balance at the early maternal-fetal interface remain mostly unknown. Methods: First-trimester decidual tissues were collected from normal pregnant women undergoing elective pregnancy terminations and patients with spontaneous abortion. We measured the expression of placental growth factor (PlGF) and Fms-like-tyrosine-kinase receptor 1 (FLT-1), and characterized the profiles of macrophages in decidua. Notably, we investigated the effect of recombinant human PlGF (rhPlGF) on decidual macrophages (dMφs) from normal pregnancy and revealed the underlying mechanisms both in vitro and in vivo. Results: The downregulated expression of PlGF/ FLT-1 may result in spontaneous abortion by inducing the M1-like deviation of macrophages in human early decidua. Moreover, the CBA/J×DBA/2 abortion-prone mice displayed a lower FLT-1 expression in uterine macrophages than did CBA/J×BALB/c control pregnant mice. In in vitro models, rhPlGF treatment was found to drive the M2-like polarization of dMφs via the STAT3/CEBPB signaling pathway. These findings were further supported by a higher embryo resorption rate and uterine macrophage dysfunction in Pgf knockout mice, in addition to the reduced STAT3 transcription and C/EBPß expression in uterine macrophages. Discussion: PlGF plays a key role in early pregnancy maintenance by skewing dMφs toward an M2-like phenotype via the FLT-1-STAT3-C/EBPß signaling pathway. Excitingly, our results highlight a rationale that PlGF is a promising target to prevent early spontaneous abortion.

HIF­3α affects preeclampsia development by regulating EVT growth via activation of the Flt­1/JAK/STAT signaling pathway in hypoxia.

Preeclampsia (PE) is a common obstetric disease occurring after 20 weeks of gestation. Hypoxia­inducible factor (HIF)­3α potentially functions as a regulatory factor in PE development, however its specific molecular mechanism remains to be elucidated. The present study aimed to investigate the function of HIF­3α in trophoblast cell line HTR­8/SVneo, to provide a better understanding of the pathology and treatment of PE. Normal and PE placentas were obtained from pregnant women. HTR8/SVneo cells were cultured under the condition of normoxia or hypoxia, pretreated with or without AG490, then transfected with HIF­3α. The gene expression levels of HIF­3α and Fms like tyrosine kinase receptor (Flt) 1 extracted from the placentas and cells were detected by reverse transcription­quantitative PCR, and the expression levels of proteins and Janus kinase signal transducer and activator of transcription (JAK/STAT) phosphorylation were detected by western blot analysis. Viability and apoptosis of the treated cells were assessed by MTT and flow cytometry. The results demonstrated that HIF­3α and Flt­1 gene expression levels of PE placentas were reduced compared with normal placentas. Under a hypoxic environment, the expression levels of HIF­3α and Flt­1, the phosphorylation of JAK/STAT and the cell viability of HTR8/SVneo cells were increased at first and then reduced, whereas cell apoptosis was promoted over time. Under chronic hypoxia, the expression levels of HIF­3α and Flt­1, JAK/STAT pathway phosphorylation and cell viability of AG490­treated HTR8/SVneo cells were reduced, but cell apoptosis was promoted. However, the upregulation of HIF­3α in HTR8/SVneo cells markedly reversed the effects of AG490 on the cells under hypoxia. Thus, the present study preliminarily demonstrated that HIF­3α was involved in PE development by regulating extravillous cytotrophoblast growth via Flt­1 and the JAK/STAT signaling pathway.

Placenta growth factor and sFlt-1 as biomarkers in ischemic heart disease and heart failure: a review.

Coronary heart disease (CHD) and heart failure (HF) produce significant morbidity/mortality but identifying new biomarkers could help in the management of each. In this article, we summarize the molecular regulation and biomarker potential of PIGF and sFlt-1 in CHD and HF. PlGF is elevated during ischemia and some studies have shown PlGF, sFlt-1 or PlGF:sFlt-1 ratio, when used in combination with standard biomarkers, strengthens predictions of outcomes. sFlt-1 and PlGF are elevated in HF with sFlt-1 as a stronger predictor of outcomes. Although promising, we discuss additional study criteria needed to confirm the clinical usefulness of PlGF or sFlt-1 in the detection and management of CHD or HF.

Reduced angiogenic factor expression in intrauterine fetal growth restriction using semiquantitative immunohistochemistry and digital image analysis.

AIM: To localize, quantify and compare angiogenic factors, vascular endothelial growth factor (VEGF), placental growth factor (PlGF), as well as their receptors fms-like tyrosine kinase receptor (Flt-1) and kinase insert domain receptor (KDR) in the placentas of normal pregnancy and complications of preeclampsia (PE), intrauterine fetal growth restriction (IUGR) and PE + IUGR. METHODS: In a prospective cross-sectional case-control study, 30 pregnant women between 24-40 weeks of gestation, were recruited into four clinical groups. Representative placental samples were stained for VEGF, PlGF, Flt-1 and KDR. Analysis was performed using semiquantitative methods and digital image analysis. RESULTS: The overall VEGF and Flt-1 were strongly expressed and did not show any conclusive difference in the expression between study groups. PlGF and KDR were significantly reduced in expression in the placentas from pregnancies complicated by IUGR compared with normal and preeclamptic pregnancies. CONCLUSION: The lack of PlGF and KDR may be a cause for the development of IUGR and may explain the loss of vasculature and villous architecture in IUGR. Automated digital image analysis software is a viable alternative method to the manual reading of placental immunohistochemical staining.

Use of serum and urinary soluble sFlt-1 and PLGF in the diagnosis of preeclampsia.

OBJECTIVE: Preeclampsia (PE) is a disorder of pregnancy marked by hypertension and proteinuria with no known treatment aside from pregnancy termination. The pathogenesis of PE is poorly understood, but is thought to originate in the placenta. We assessed the value of measuring serum and urinary soluble deformylase-like tyrosine kinase receptor 1 (sFlt-1), a known target of placental factors, and placental growth factor (PLGF), a key placental signaling molecule, in the diagnosis of PE. METHODS: Eighty patients with PE were classified as either exhibiting mild (44 cases) or severe (36 cases) symptoms of PE. Forty normal pregnant women were selected as controls. Serum and urinary PLGF and sFlt-1 levels, along with the ratio of sFlt-1 to PLGF, were compared across groups. RESULTS: Serum and urinary sFlt-1 and sFlt-1/PLGF ratios in severe PE patients were significantly higher than those in the mild PE group, and measurements from mild PE patients were significantly higher than controls (all P values <0.01). The serum and urinary PLGF levels in severe PE patients were significantly lower than mild PE patients, and mild PE patients had significantly lower PLGF levels than controls (all P values <0.01). As expected, serum sFlt-1 and PLGF levels and ratios were highly correlated with urinary sFlt-1 and PLGF levels and ratios. CONCLUSIONS: The severity of PE was closely correlated with these measurements, suggesting that they may be useful tools in the diagnosis and evaluation of PE.