Short communicationNicotinamide and its effects on endothelial dysfunction and secretion of antiangiogenic factors by primary human placental cells and tissues
Introduction
Preeclampsia is a serious pregnancy complication with no treatment. It is associated with increased placental secretion of antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) [[1], [2], [3]] and soluble endoglin (sENG) [4]. It is also associated with reduced circulating angiogenic markers placental growth factor (PlGF) and vascular endothelial growth factor α (VEGFα) [[5], [6], [7]]. This culminates in widespread endothelial dysfunction. Our field is focused on developing a medical treatment for preeclampsia, despite promising preclinical data, a positive effect in clinical trials has been elusive [8,9].
Nicotinamide, vitamin B3, a medication that is safe in pregnancy, has shown promise in animal studies as a potential treatment for preeclampsia [10,11]. Using three different preeclampsia mouse models [10,11] one group have demonstrated nicotinamide can rescue features of preeclampsia. Specifically, nicotinamide reduced blood pressure, endotheliosis and improved pup weights and survival [10,11]. Given these findings, the authors have advocated for nicotinamide clinical trials for prevention or treatment of preeclampsia. A small single arm clinical trial assessing the effect of nicotinamide in 25 women with preeclampsia is registered (NCT3419364).
The effect of nicotinamide on characteristics of preeclampsia in primary human tissues has not been explored. Given nicotinamide is thought to alter metabolic pathways and reduce the impact of hypoxia, processes that have been shown to upregulate antiangiogenic factor secretion, we were interested to explore its effect of antiangiogenic factor secretion and angiogenic factor expression from primary human tissues. As nicotinamide prevented hypertension in animal models of preeclampsia we were interested to explore its effect on markers of endothelial dysfunction known to be upregulated in preeclampsia using primary endothelial cells.
Section snippets
Materials and methods
We performed functional experiments to explore the effect of nicotinamide on primary human pregnancy tissues. The full methods are outlined in the supplementary.
Results
Effect of nicotinamide on antiangiogenic factor sFlt-1 and sENG secretion and angiogenic factor PlGF and VEGF expression from placental tissues.
To examine the functional effect of nicotinamide on placental secretion of antiangiogenic factors and expression of angiogenic factors we obtained placental explants and isolated cytotrophoblasts and treated these with nicotinamide. Increasing doses of nicotinamide did not change sFlt-1 and sENG secretion from placental explants or cytotrophoblasts (
Discussion
There has been interest in nicotinamide as a possible therapy for preeclampsia stemming from work by Li et al. [10], demonstrating nicotinamide ameliorated preeclampsia like features in mouse models. Utilising primary human tissues we show nicotinamide had no effect on antiangiogenic factor secretion or on key markers of endothelial dysfunction.
The lack of an effect on sFlt-1 secretion from primary human tissues is in keeping with animal studies [10]. Utilising an adenoviral vector sFlt-1
Author contributions
FCB and NJH designed the experiments and wrote the main manuscript. NB, AH, SB and LT were involved in data generation. All authors reviewed the manuscript and provided intellectual input and approved the manuscript.
Funding
FB was supported by a NHMRC Early Career Fellowship (#1142636) and a Norman Beischer Medical Research Foundation Fellowship grant. The NHMRC also provided salary support to ST (#1136418) and NJH (#1146128). The funders had no role in study design, data collection, analysis, decision to publish or the preparation of the manuscript.
Declaration of competing interest
The authors report no conflict of interest.
Acknowledgements
We would like to thank the research midwives, Gabrielle Pell, Genevieve Christophers, Rachel Murdoch and Debra Jinks, and patients at Mercy Hospital for Women for participating in this research.
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