First trimester placental endothelial cells from pregnancies with abnormal uterine artery Doppler are more sensitive to apoptotic stimuli

Abstract

Failure of the placental capillary network to develop normally is associated with early onset fetal growth restriction (FGR) and pre-eclampsia (PE). Although the symptoms are observed at term, the problem begins in the first trimester. However, investigations at this clinically relevant time are hindered by difficulties in identifying earlystage pregnancies that are at risk of developing FGR/PE. Using uterine artery Doppler ultrasound in the first trimester as a proxy measure of poor placentation, we have identified pregnancies at increased risk of developing early onset FGR/PE. Placental endothelial cells (PEC) isolated from pregnancies at increased risk of developing FGR/PE grew more slowly and their basal rate of apoptosis was significantly higher than that seen in the normal group. The pro-apoptotic stimulus, TNFα, induced apoptosis in cells from both groups but this was significantly greater in the high risk group. TNF receptor expression was unaffected. Inhibition of nitric oxide (NO) production significantly increased the sensitivity of cells from the normal pregnancies to TNFα but not in the high risk group establishing a functional role for NO in this system. In conclusion, first trimester PEC from pregnancies at increased risk of developing early onset FGR/PE were inherently more sensitive to apoptotic stimuli and this was functionally linked to the synthesis of NO. This may contribute to the poor placental vascular development seen in on going pregnancies.

Preeclampsia: a gestational cardiorenal syndrome

“…However, more recent evidence has demonstrated that uterine artery Doppler waveforms better reflect maternal systemic vascular resistance rather than local uterine artery resistance (Kalafat et al 2018;Perry et al 2018c). The latter data would indicate that maternal uterine perfusion dictates the degree of placental invasion rather than the other way round -a hypothesis which is consistent with cellular and mechanistic studies of trophobalsat function (Leslie et al 2015;Wallace et al 2015;James-Allan et al 2018;Charolidi et al 2019).…”

Preeclampsia: The Relationship between Uterine Artery Blood Flow and Trophoblast Function

“…Several studies have shown that placental tissues obtained from women with high-resistance uterine artery Doppler indices were more sensitive to apoptotic stimuli than placental tissue from women with normal indices [8,9,10]. Charolidi et al examined the effect of tumor necrosis factor alpha (TNFα) on placental endothelial cell (PEC) apoptosis in the context of high vs. normal uterine artery Dopplers (Figure 1).…”

“…Charolidi et al examined the effect of tumor necrosis factor alpha (TNFα) on placental endothelial cell (PEC) apoptosis in the context of high vs. normal uterine artery Dopplers (Figure 1). They demonstrated that placental endothelial cells (PECs) from the high resistance index (RI) group exposed to TNFα had a 40% reduction in half-life compared to those from the normal RI group which were exposed to TNFα [10].…”

Cell-specific characterization of the placental methylome

“…Placental vasculature is critically important for proper functioning of the placenta, and depends on the development of vessels beneath the trophoblast layer. These vessels are formed from endothelial cells (EC) that derive from the chorionic mesoderm [ 9 ]. Encompassing the mesenchymal core is a thick trophoblast (TB) epithelial cell layer, which displays a hypomethylated profile [ 10 ].…”