The placental factor theory of preeclampsia Preeclampsia is a pregnancy-specific condition characterized by
maternal hypertension and
proteinuria after the 20th week of
gestation. Specifically, invading cytotrophoblasts achieve this change by down-regulating the expression of
adhesion molecules characteristic of
epithelial cells and up-regulating the expression of adhesion molecules characteristic of
endothelial cells in a process known as pseudovasculogenesis. In preeclamptic patients, this arterial transformation is incomplete, as cytotrophoblasts fail to completely switch their adhesion molecule expression pattern to an endothelial form. The balance of pro- and anti-angiogenic factors and their receptors, including
VEGF-A, PIGF, Flt1, and sFlt1, is thought to mediate this process. Expression of sFlt-1 is stimulated by
hypoxic conditions. In healthy pregnancies, the placenta develops in a hypoxic environment, leading to a 20-fold increase in sFlt-1 expression. In early-onset preeclamptic patients, this increase is estimated to be up to 43 times more pronounced, and may be spurred by conditions of poor
uterine profusion leading to more severe local hypoxia. Inhibition of
nitric oxide signaling has also been associated with elevation of serum sFlt-1 in a rat model of preeclampsia; this stimulus may represent a secondary factor contributing to sFlt-1 trends in human preeclampsia as well. In addition to short-term regulation by oxygen and nitric oxide levels, genetic differences also influence Flt-1 gene splicing and resulting sFlt-1 expression levels. Women with histories of preeclampsia continue to show elevated serum levels of sFlt-1 up to 18 months
postpartum, suggesting a genetic basis of sFlt-1 expression independent of pregnancy-related stimuli.
Clinical significance PlGF and sFlt-1 concentrations measured by
immunoassay in maternal blood improve the prognostic possibilities in preeclampsia, which is typically diagnosed solely on the basis of clinical symptoms, proteinuria, and
uterine artery Doppler velocimetry. Notably, increases in sFlt-1 and decreases in PIGF and VEGF can be detected at least five weeks before the onset of preeclamptic symptoms, potentially facilitating earlier diagnosis and treatment. sFlt-1 changes are most predictive of early-onset preeclampsia; cases of preeclampsia incident late in pregnancy typically are accompanied only by small decreases in PIGF. Additionally,
sensitivity and specificity of sFlt-1 testing is generally considered too low to enable it to serve as an effective predictor of preeclampsia. sFlt-1 involvement in the pathogenesis of preeclampsia may explain several demographic trends in incidence of the condition. The human Flt-1/sFlt-1 gene is located at
13q12; the association of fetal
trisomy-13 with higher rates of preeclampsia could theoretically be explained by the additional copy of the gene. Additionally,
primiparous women have higher baseline levels of sFlt-1, a trend which could potentially explain the higher incidence of preeclampsia among first-time mothers. == Citations ==