Melatonin, a Potential Therapeutic Agent for Preeclampsia, Reduces the Extrusion of Toxic Extracellular Vesicles from Preeclamptic Placentae.

Yunhui Tang,Katie Groom,Qi Chen,Larry Chamley

doi:10.3390/cells10081904

Yunhui Tang, Katie Groom + Show 2 more

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https://doi.org/10.3390/cells10081904

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Journal: Cells	Publication Date: Jul 27, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: Auckland City Hospital, University of Auckland

Abstract

Preeclampsia, characterised by maternal endothelial cell activation, is triggered by toxic factors, such as placental extracellular vesicles (EVs) from a dysfunctional placenta. The increased oxidative stress seen in the preeclamptic placenta links to endoplasmic reticulum (ER) stress. The ER regulates protein folding and trafficking. When the ER is stressed, proteins are misfolded, and misfolded proteins are toxic. Misfolded proteins can be exported from cells, via EVs which target to other cells where the misfolded proteins may also be toxic. Melatonin is a hormone and antioxidant produced by the pineal gland and placenta. Levels of melatonin are reduced in preeclampsia. In this study we investigated whether melatonin treatment can change the nature of placental EVs that are released from a preeclamptic placenta. EVs were collected from preeclamptic (n = 6) and normotensive (n = 6) placental explants cultured in the presence or absence of melatonin for 18 h. Misfolded proteins were measured using a fluorescent compound, Thioflavin-T (ThT). Endothelial cells were exposed to placental EVs overnight. Endothelial cell activation was measured by the quantification of cell-surface ICAM-1 using a cell-based ELISA. EVs from preeclamptic placentae carried significantly (p < 0.001) more misfolded proteins than normotensive controls. Incubating preeclamptic placental explants in the presence of melatonin (1 µM and 10 µM) significantly (p < 0.001) reduced the misfolded proteins carried by EVs. Culturing endothelial cells in the presence of preeclamptic EVs significantly increased the expression of ICAM-1. This increased ICAM-1 expression was significantly reduced when the endothelial cells were exposed to preeclamptic EVs cultured in the presence of melatonin. This study demonstrates that melatonin reduces the amount of misfolded proteins carried by EVs from preeclamptic placentae and reduces the ability of these EVs to activate endothelial cells. Our study provides further preclinical support for the use of melatonin as a treatment for preeclampsia.

Highlights

Preeclampsia, a human specific pregnancy disorder, is clinically characterised by high blood pressure after 20 weeks of gestation accompanied by one or more of a spectrum of signs of organ dysfunction [1,2]
Both the micro-Extracellular vesicles (EVs) and nano-EVs released from preeclamptic placental explants that had been incubated with melatonin did not induce an increase in endothelial cell activation
These placental EVs from preeclamptic placentae may contribute to triggering the disease by inducing maternal systemic endothelial cell dysfunction [42], as they carry several anti-angiogenic factors, including soluble fms-like tyrosine kinase-1 and soluble Endoglin, cytokines and oxidants, as well as multiple “danger” signals [43]

Summary

Introduction

Preeclampsia, a human specific pregnancy disorder, is clinically characterised by high blood pressure after 20 weeks of gestation accompanied by one or more of a spectrum of signs of organ dysfunction [1,2]. It affects 2–8% of all pregnancies worldwide [1,2]. Extracellular vesicles (EVs) are among the placental factors that are increasingly recognised as being able to contribute to the endothelial cell dysfunction of preeclampsia [4,5,6]

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