Maternal sFLT1 and EDN1 linked to late-onset preeclampsia

Maternal sFLT1 and EDN1 linked to late-onset preeclampsia | Image Credit: © Prostock-studio - © Prostock-studio - stock.adobe.com.

Maternal soluble Fms-like tyrosine kinase 1 (sFLT1) may be associated with late-onset preeclampsia (LOPE), according to a recent study published in the American Journal of Obstetrics & Gynecology.¹

There is significant heterogeneity in the clinical progression of preeclampsia, leading to a lack of knowledge about the disease’s pathogenesis. Categories of preeclampsia include early-onset preeclampsia (EOPE) and LOPE, determined by diagnosis before or after 34 weeks’ gestation.

Increased maternal sFLT1 has been observed in preeclampsia patients, alongside increased maternal soluble endoglin (sENG) with potential placental origin. The potent vasoconstrictor endothelin 1 (EDN1) may be stimulated by sENG, and EDN1 has associations with the pathogenesis of preeclampsia.

There is little information about placental release and factors impacting angiogenesis and vessel tone on the fetal side of the placenta. While EDN1 levels are higher in fetal circulation vs maternal circulation, no differences have been reported between preeclampsia status.²

Investigators conducted a 4-vessel case control study to compare protein abundance in maternal and fetal vessels between healthy pregnancies, EOPE, and LOPE.¹ Participants included healthy singleton pregnancies scheduled for cesarean delivery between October 2012 and June 2015.

Women who were smoking, with a preexisting comorbidity or pregnancy complications, or with onset of labor were excluded from the analysis. Sampling was performed in the maternal radial artery, antecubital vein, and uterine vein on the anterolateral surface of the uterus.

In 75 of 179 healthy pregnancies, 19 EOPE cases, and 18 LOPE cases, investigators performed protein quantification. A new-onset blood pressure of at least 140/90 mmHg and proteinuria following week 20 of gestation indicated the presence of preeclampsia.

Protein quantification was performed using SomaLogic’s microarray-based SomaScan assay version 4.0. Two aptamers were used to quantify sFLT1.

Preeclampsia patients had increased rates of nulliparity, and small for gestational age fetuses were more common in the EOPE group than the LOPE and healthy pregnancy groups. EOPE also had reduced placental growth factor (PGF) compared to these groups.

Both LOPE and EOPE pregnancies had increased maternal sFLT1 compared to healthy pregnancies. The most significant amount of sFLT1 was observed in EOPE pregnancies. Increased sENG was also observed in EOPE and LOPE pregnancies in the radial artery.

LOPE pregnancies had reduced sENG compared to healthy pregnancies, while EOPE pregnancies had significant variation in fetal sENG. For EDN1, patterns were similar across maternal vessels to sFLT1. EOPE pregnancies had increased fetal EDN1 in the umbilical vessels compared to healthy pregnancies and the umbilical artery compared to LOPE.

Placental release of PGF, sFLT1, EDN1, EDN2, and EDN3 to the maternal circulation were observed in healthy pregnancies based on the 4-vessel model. For LOPE and EOPE, placental release of PGF and sFLT1 were observed.

All groups displayed significantly increased PGF and sFLT1 in the uterine vein vs the antecubital vein. Placental release of sFLT1 and sENG into fetal circulation occurred in healthy pregnancies. While placental release of sFLT1 occurred in LOPE, placental uptake of PGF and EDN3 were also observed.

Healthy pregnancies had higher maternal PGF, sFLT1, and EDN3, but lower EDN1 and EDN2 vs fetal abundance. For LOPE, maternal PGF, sFLT1, sENG, and EDN3 were higher but EDN2 lower. Finally, EOPE had higher maternal PGF, sFLT1 and EDN3, but lower EDN2.

These results indicated significant increases in maternal sFLT1, EDN1, and EDN2 in preeclampsia vs healthy pregnancies. Investigators concluded sFLT1 and EDN1 may be associated with the pathophysiology and severity of preeclampsia.

References

1. Westerberg AC, Degnes MHL, Andresen IJ, et al. Angiogenic and vasoactive proteins in the maternal-fetal interface in healthy pregnancies and preeclampsia. Am J Obstet Gynecol. 2024;231:550.e1-22. doi:10.1016/j.ajog.2024.03.012
2. Wolff K, Nisell H, Carlström K, et al Endothelin-1 and big endothelin-1 levels in normal term pregnancy and in preeclampsia. Regul Pept. 1996;67(3):211-6. doi:10.1016/s0167-0115(96)00122-x