Transcriptionally Active Syncytial Aggregates in the Maternal Circulation May Contribute to Circulating Soluble Fms-Like Tyrosine Kinase 1 in Preeclampsia

Abstract

The cardinal manifestations of the pregnancy-specific disorder preeclampsia, new-onset hypertension and proteinuria that resolve with placental delivery, have been linked to an extracellular protein made by the placenta, sFlt1 (soluble fms-like tyrosine kinase 1), that injures the maternal vasculature. However, the mechanisms by which sFlt1, which is heavily matrix-bound, gains access to the systemic circulation remain unclear. Here we report that the preeclamptic placenta’s outermost layer, the syncytiotrophoblast, forms abundant “knots” that are enriched with sFlt1 protein. These syncytial knots easily detach from the syncytiotrophoblast, resulting in free, multinucleated aggregates (50–150 μm diameter) that are loaded with sFlt1 protein and mRNA, are metabolically active, and are capable of de novo gene transcription and translation. At least 25% of the measurable sFlt1 in 3rd trimester maternal plasma is bound to circulating placental microparticles. We conclude that detachment of syncytial knots from the placenta results in free, transcriptionally active syncytial aggregates that represent an autonomous source of sFlt1 delivery into the maternal circulation. The process of syncytial knot formation, shedding of syncytial aggregates, and appearance of placental microparticles in the maternal circulation appears to be greatly accelerated in preeclampsia and may contribute to the maternal vascular injury that characterizes this disorder.

Angiogenic Factors in Preeclampsia

“…39 Although placenta is the major source of sFlt1 production, immunohistochemistry studies have suggested that syncytial knots (degenerating syncytiotrophoblast tissue) in the placenta is the major site of sFlt1 production. 40,41 These syncytial knots easily detach from the syncytiotrophoblast, resulting in free, multinucleated aggregates (50-to 150-μm diameter) that are loaded with sFlt1 protein and mRNA, and are capable of de novo gene transcription and translation. 40,42 Other studies using autopsy material have suggested that shed syncytial knots may contribute to circulating sFlt1 in preeclampsia.…”

“…40,41 These syncytial knots easily detach from the syncytiotrophoblast, resulting in free, multinucleated aggregates (50-to 150-μm diameter) that are loaded with sFlt1 protein and mRNA, and are capable of de novo gene transcription and translation. 40,42 Other studies using autopsy material have suggested that shed syncytial knots may contribute to circulating sFlt1 in preeclampsia. 43 Because these synytial microparticles are of fetal origin, this process of syncytial microparticle shedding may lead to chimerism, as fetal cells can be retained in the maternal blood and organs for decades after delivery.…”

Oxidative stress, placental ageing‐related pathologies and adverse pregnancy outcomes

“…93 This disorder develops during pregnancy, and the rapid and complete recovery after childbirth indicates that the placenta has a pivotal role in the pathogenesis of this disease. 94 Although the aetiology of pre-eclampsia is still subject to debate, the basic pathologic event in pre-eclampsia is an injury to the vascular endothelium 95 that is mediated by OS from increased placental ROS or decreased antioxidant activity. 96 Consequently, trophoblastic invasion to the spiral arteries is inhibited that limits the spiral artery remodelling to the decidual portions and the myometrial segments of the arteries remain narrow and contractile.…”

Nitroso-Redox Balance and Mitochondrial Homeostasis Are Regulated bySTOX1, a Pre-Eclampsia-Associated Gene

“…Transitory local hypoxic/hyperoxic changes exceedingly erode the syncytiotrophoblast and shed debris into maternal circulation. These debris release vasoactive substances such as endothelin 1 (55) and antiangiogenic factors (notably sFLT-1 and sENG), thus contributing to the maternal systemic endothelial injury.…”