Original ResearchObstetricsMetformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction
Section snippets
Objective
This study had 3 objectives: (1) to assess the effects of metformin on sFlt-1 and sENG secretion from primary placental and endothelial cells/tissues and to investigate whether these effects are mediated through mitochondrial electron transport chain inhibition; (2) to assess whether mitochondrial electron transport chain activity positively regulates sFlt-1 secretion and if preterm preeclamptic placenta have increased mitochondrial electron transport chain activity; and (3) to assess whether
Patient population
We performed functional experiments in which we administered metformin to human tissues and assessed its effects on sFlt-1 and sENG secretion, mitochondrial electron transport chain function, and endothelial dysfunction. To perform our experiments, we examined tissues from placenta and blood vessels.
We collected several types of placental tissues. We isolated human umbilical vein endothelial cells (HUVECs)63 and primary villous cytotrophoblast cells64 from the placenta and umbilical cord that
Metformin reduces sFlt-1 secretion from primary endothelial cells and placental tissues
We assessed the effects of metformin on sFlt-1 secretion from endothelial and placental tissues because they are its main tissue source. Administering metformin dose-dependently reduced sFlt-1 secretion from endothelial cells (HUVECs; Figure 1, A) and primary cells that were isolated from placenta (villous cytotrophoblast cells; Figure 1, B). At the highest doses, metformin reduced endothelial and placental cell secretion by 53% and 63%, respectively. Metformin also reduced sFlt-1 secretion
Primary findings of the study
Metformin reduces sFlt-1 and sENG secretion from primary human tissues, possibly by inhibiting the mitochondrial electron transport chain. Second, mitochondrial electron transport chain activity positivity regulates sFlt-1 secretion, and mitochondrial electron transport chain activity is increased in preterm preeclamptic placenta. By using assays to replicate the endothelial and vascular dysfunction that may be occurring in preeclampsia, we found that metformin reduces endothelial dysfunction,
Acknowledgments
We thank the research midwives, Gabrielle Pell, Genevieve Christophers, Rachel Murdoch, and Debra Jinks, and the patients at Mercy Hospital for Women for participating in this research.
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Supported by The National Health and Medical Research Council of Australia (NHMRC; #1048707, #1046484, #1101871) and an Arthur Wilson RANZCOG scholarship; by an Australian Postgraduate Award and an AVANT scholarship (F.B); by a CR Roper Research Fellowship (N.J.R.); the NHMRC provided salary support (#1050765 [S.T.]; #1062418 [T.K.L.]; #628549 [S.S.]). The funders had no role in study design, data collection, analysis, decision to publish or the preparation of the manuscript.
The authors report no conflict of interest.
Cite this article as: Brownfoot FC, Hastie R, Hannan NJ, et al. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol 2016;214:356.e1-15.
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These authors have contributed equally to this article.