As a VEGF receptor, Flt-1 is highly expressed in the invading extravillous trophoblasts in the first trimester, which implies that VEGF-Flt-1 interactions lead to early trophoblast invasion
[43]. As gestational age develops, VEGF-Flt-1 interaction also guides trophoblast differentiation and migration
[44]. Soluble FMS-like tyrosine kinase I (sFlt-1) is a truncated protein resulting from splicing of Flt-1 which lacks the cytoplasmic and transmembrane domain but keeps the ligand-binding domain
[45]. Therefore, sFlt-1 antagonizes and inhibits VEGF and PlGF by binding to them and blocking their interaction with Flt-1 for proangiogenic function. In preeclampsia, placental ischemia resulting from RUPP may stimulate upregulation of sFlt-1 by binding of hypoxia inducible factor (HIF) to the promotor of Flt-1 gene
[38]. The elevated maternal serum level of sFlt-1 in preeclampsia has been found to be associated with severe endothelial dysfunction and inhibition of VEGF and PlGF by sFlt-1 serves a major pathogenic role in hypertension and proteinuria
[1]. VEGF is responsible for decreasing vascular tone and blood pressure by inducing nitric oxide and prostacyclins that have a vasodilatory effect in endothelial cells, which is blocked by sFlt-1. In addition, several molecular mechanisms of sFlt-1 found to be responsible for renal dysfunction are related to glomerular capillary endotheliosis, dysregulation of the glomerular filtration apparatus, and podocyte loss
[46]. Therefore, excess of sFlt-1 results in the characteristic antiangiogenic state of preeclampsia which manifests as the clinical syndrome of endothelial dysfunction. In fact, maternal serum level of sFlt-1 to PlGF ratio (sFlt-1/PlGF ratio) can be used as a reliable biomarker for predicting development and severity of preeclampsia
[47]. Moreover, a recent systematic review and meta-analysis on the performance of the sFlt-1/PlGF ratio in predicting adverse outcomes in women diagnosed or suspected of preeclampsia showed that the sFlt-1/PlGF ratio performs better in predicting women with early onset preeclampsia in comparison to those with late onset
[48]; this relates to our previous topic in chapter 4 which described that defective uteroplacental vascular remodeling is mostly seen in the early onset type of preeclampsia.