Oxygen and the liberation of placental factors responsible for vascular compromise

Abstract

Maternal endothelial activation in pre-eclampsia is attributed to the release of unknown factors from a hypoperfused placenta. To further characterize these factors, we have used a serum-free placental villous explant culture model and investigated the effect of the liberated soluble factors produced on human endothelial cell cultures. Term placental villous explants from uncomplicated pregnancies were cultured for 4 days in 20, 6 or 1% O 2 to mimic placental hyperoxia, normoxia and hypoxia. Medium collected from viable explants was applied to cultured human uterine microvascular endothelial cells. Medium conditioned by hypoxic explants caused a significant decrease in endothelial cell ATP levels and mitochondrial dehydrogenase activity, suggestive of a reduced metabolic rate. An additional reduction in mitochondrial membrane potential and increased endothelial cell death occurred as the oxygen concentration to which explants had been exposed decreased. Effects of the hypoxic explant medium were also seen ex vivo in a wire myography model of myometrial artery function, with increased vasoconstriction and attenuated vasodilation following exposure to hypoxic explant medium. These results suggest that hypoxia (1% O 2 ) may stimulate the release of soluble factors from the placenta, which have an adverse effect on endothelial cell metabolism and mitochondrial integrity in vitro. These potentially pathogenic factors are now being characterized.

Analysis of Nitric Oxide Metabolism as a Placental or Maternal Factor Underlying the Etiology of Pre-Eclampsia

“…One plausible hypothesis for this role is that the hypoperfused placenta releases unknown soluble factors that contribute to maternal endothelial activation, leading to the onset of pre-eclampsia [11,12,14] . In this context, reduced NOS activity in the placenta may be a trigger for vasoconstriction therein.…”

Recapitulating physiological and pathological shear stress and oxygen to model vasculature in health and disease

“…It is well established that the hypoxic conditions (≤5%) alter endothelial phenotype and permeability8910. We and others have shown that cultured ECs respond differently when at physiological O 2 (5–12%) compared to conventional atmospheric O 2 (21% O 2 )1112. Overall, while the individual effects of varying shear stress and O 2 tension on angiogenesis have been studied, creating an in vitro system with control over both shear stress and O 2 levels will advance our understanding and predictability of human endothelial functionality in healthy and diseased conditions.…”

Proteomics Approaches in Pre-Eclampsia Research

“…We have recently used a hypoxic placental explant model to study factors present in serum-free explant-conditioned media and their effect on endothelial cell function. 48 Factors capable of altering endothelial function were demonstrated in explant-conditioned media generated from placental explants cultured under hypoxic conditions (1% vs 6% O 2 ) using several different endothelial bioassays. In our laboratories, we have used a MS-based approach to identify differences in proteins released into placental explant-conditioned media under normoxic and hypoxic conditions.…”