Hypoxic trophoblast-derived sFlt-1 may contribute to endothelial dysfunction: An implication for the mechanism of trophoblast-endothelial dysfunction in preeclampsia

Abstract

The maternal systemic disorder of widespread endothelial dysfunction is a primary focus in understanding the development of preeclampsia. sFlt-1 (soluble fms-like tyrosine kinase receptor 1), an endogenous inhibitor of VEGF (vascular endothelial growth factor), may play important roles in endothelial dysfunction. The present study aimed to determine whether hypoxic trophoblast-derived sFlt-1 could lead to endothelial dysfunction by establishing a cocultured model of anoxic TEV-1s (human first-trimester extravillous trophoblasts) and HUVECs (human umbilical vein endothelial cells). The results showed that the hypoxic treatment significantly promoted sFlt-1 mRNA and protein expression in TEV-1s in a time-dependent manner compared with the effect in HUVECs. When HUVECs were cocultured with anoxic TEV-1s, the endothelial function, which was characterized by NO (nitric oxide) synthesis and monolayer barrier function of HUVECs, were notably decreased, accompanied by increasing sFlt-1 and decreasing VEGF in cell-conditioned medium. Moreover, the observed endothelial dysfunction described above was consistent with the dysfunction observed in VEGF siRNA-treated cultures. The findings presented herein imply that chronically hypoxic trophoblasts may release sufficient sFlt-1 to cause endothelial dysfunction by depriving cells of VEGF activity.

Thrombin enhances soluble Fms-like tyrosine kinase 1 expression in trophoblasts; possible involvement in the pathogenesis of preeclampsia

“…Maynard et al (6) were the first to demonstrate hypertension, proteinuria, and edema in pregnant rats as a result of the administration of sFlt-1, suggesting that excess circulating sFlt-1 contributes to the pathogenesis of preeclampsia. Other groups, including the present authors, have also reported that circulating levels of sFlt-1 are elevated in preeclampsia (7)(8)(9)(10)(11) and diseases that cause preeclampsia, such as molar pregnancy (12). Given its strong involvement in the pathogenesis of preeclampsia, attempts to identify factors that regulate sFlt-1 expression in trophoblasts have been made with the aim to investigate possible novel strategies for managing this condition.…”

The Pivotal Role of the Placenta in Normal and Pathological Pregnancies: A Focus on Preeclampsia, Fetal Growth Restriction, and Maternal Chronic Venous Disease

“…sFlt-1 binds to free VEGF and PlGF, thereby limiting the bioavailability of these angiogenic components [134]. Chronic hypoxic trophoblasts are responsible for a sustained sFlt-1 release that indeed is sufficient to cause endothelial dysfunction in vitro [135]. This effect is amplified when sFlt-1 acts with sEng, which impairs the binding of TGF-β1 to its receptors and its downstream signaling in the vasculature [136].…”

Endothelial dysfunction and preeclampsia: role of oxidative stress

“…One of the mechanisms of ED involves release of the sFlt-1 (soluble fms-like tyrosine kinase or sVEGFR1), which is a circulating anti-angiogenic protein and an endogenous inhibitor of vascular endothelial growth factor (VEGF), that works by enhancing the ED already established by oxidative stress, ROS and damage (Sato et al, 2000 ; Luttun et al, 2002 ; Maynard et al, 2003 ; López-Novoa, 2007 ; Widmer et al, 2007 ; Zhou et al, 2011 ; Murphy et al, 2013 ) (Figure 2 ). VEGF is key in the process of growth of new blood vessels and in the overall maintenance and endothelial cell health.…”