Increased Placental sFLT1 (Soluble fms-Like Tyrosine Kinase Receptor-1) Drives the Antiangiogenic Profile of Maternal Serum Preceding Preeclampsia but Not Fetal Growth Restriction

Abstract

Background: Preeclampsia and fetal growth restriction (FGR) are both associated with an increased ratio of sFLT1 (soluble fms-like tyrosine kinase-1) to PlGF (placenta growth factor) in maternal serum. In preeclampsia, it is assumed that increased placental release of sFLT1 results in PlGF being bound and inactivated. However, direct evidence for this model is incomplete, and it is unclear whether the same applies in FGR.

Methods: We conducted a prospective cohort study where we followed 4212 women having first pregnancies from their dating ultrasound, obtained blood samples serially through the pregnancy, and performed systematic sampling of the placenta after delivery. The aim of the present study was to determine the relationship between protein levels of sFLT1 and PlGF in maternal serum measured at ≈36 weeks and placental tissue lysates obtained after term delivery in 82 women with preeclampsia, 50 women with FGR, and 132 controls.

Results: The sFLT1:PlGF ratio was increased in both preeclampsia and FGR in both the placenta and maternal serum. However, in preeclampsia, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental sFLT1 level (r=0.45; P<0.0001) but not placental PlGF level (r=-0.17; P=0.16). In contrast, in FGR, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental PlGF level (r=-0.35; P=0.02) but not sFLT1 level (r=0.04; P=0.81).

Conclusions: We conclude that the elevated sFLT1:PlGF ratio is primarily driven by increased placental sFLT1 in preeclampsia, whereas in FGR, it is primarily driven by decreased placental PlGF.

Keywords: cohort studies; fetal growth retardation; placenta; placenta growth factor; preeclampsia.

Figure 1.

Placental protein levels of sFLT1 (soluble fms-like tyrosine kinase), PlGF (placenta growth factor), and the Flt1 (fms-like tyrosine kinase):PlGF ratio in pathological and healthy pregnancies. Protein levels were measured in term placentas from healthy pregnancies compared with (A–C) paired preeclamptic pregnancies (n=160 for sFLT1 and sFLT1:PlGF; n=164 for PlGF). D through F, Pregnancies with fetal growth restriction (FGR) fetuses (n=97 for sFLT1 and sFLT1:PlGF; n=100 for PlGF). Samples were omitted from the analyses if measurements were not available or below the detection limit of the assay, and protein levels are expressed as Z scores of the log-transformed concentrations. Boxes indicate the median, 25th, and 75th percentiles. Whiskers extend to the minimum and maximum values. P values, obtained using paired (A–C) or unpaired (D–F) 2-tailed t test, are reported. CON indicates control/healthy pregnancy; and PE, preeclampsia.

Figure 2.

Maternal circulating levels of sFLT1 (soluble fms-like tyrosine kinase), PlGF (placenta growth factor), and the sFlt1:PlGF ratio in pathological and healthy pregnancies. Maternal serum protein levels were measured at ≈36 weeks of gestation in 2 cohorts: (A–C) 68 paired healthy and preeclamptic pregnancies (n=136); (D–F) control pregnancies (n=48) and with fetal growth restriction (FGR) fetuses (n=46). Samples were omitted from the analyses if measurements were not available or below the detection limit of the assay. Maternal proteins are expressed as the multiple of the median (MoM) of control samples (adjusted for gestational age, maternal weight, and storage time at measurement), log transformed, and turned into Z scores. The unadjusted sFLT1:PlGF ratio was log transformed and turned into a Z score. Boxes indicate the median, 25th, and 75th percentiles. Whiskers extend to the minimum and maximum values. P values, obtained using paired (A–C) or unpaired (D–F) 2-tailed t test, are reported. CON indicates control/healthy pregnancy; and PE, preeclampsia.

Figure 3.

Relationship between placental sFLT1 (soluble fms-like tyrosine kinase) and PlGF (placenta growth factor) concentrations and maternal serum levels of sFLT1, PlGF, and the sFLT1:PlGF ratio in pregnancies with preeclampsia. Maternal sFLT1, PlGF, and the sFLT1:PlGF ratio at 36 weeks of gestation are plotted against term placental sFLT1 (A–C) or PlGF concentrations (D–F) in 69 women who ultimately delivered with a diagnosis of preeclampsia. Samples were removed from the analyses if measurements were not available or below the detection limit of the assay. Maternal proteins are expressed as the multiple of the median (MoM) of control samples (adjusted for gestational age, maternal weight, and storage time at measurement). Then MoM values and placental protein concentrations were log transformed and expressed as Z scores. Best fitting regression line (solid) and 95% confidence bands (dotted) are indicated. Text boxes report Pearson correlation coefficients (r) and P.

Figure 4.

Relationship between placental sFLT1 (soluble fms-like tyrosine kinase) and PlGF (placenta growth factor) concentrations and maternal serum levels of sFLT1, PlGF, and the sFLT1:PlGF ratio in pregnancies with fetal growth restriction. Maternal sFLT1, PlGF, and the sFLT1:PlGF ratio at 36 weeks of gestation are plotted against term placental sFLT1 (n=44; A–C) or PlGF concentrations (n=46; D–F) in pregnancies with fetal growth restriction. Samples were removed from the analyses if measurements were not available or below the detection limit of the assay. Maternal proteins are expressed as the multiple of the median (MoM) of control samples (adjusted for gestational age, maternal weight, and storage time at measurement). Then MoM values and placental protein concentrations were log transformed and expressed as Z scores. Best fitting regression line (solid) and 95% confidence bands (dotted) are indicated. Text boxes report Pearson correlation coefficients (r) and P.