Gill, Manjot, Motta-Mejia, Carolina, Kandzija, Neva, Cooke , William, Zhang, Wei, Cerdeira, Ana Sofia, Bastie, Claire C., Redman, Christopher W. and Vatish, Manu (2019) Placental syncytiotrophoblast-derived extracellular vesicles carry active NEP (Neprilysin) and are increased in preeclampsia. Hypertension, 73 (5). pp. 1112-1119. doi:10.1161/HYPERTENSIONAHA.119.12707

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Abstract

NEP (neprilysin) is a widely expressed membrane-bound metalloprotease, which binds and cleaves a variety of peptides including vasodilators, natriuretics, and diuretics. Higher levels of NEP result in hypertension-a cardinal feature of the placental disease preeclampsia. Syncytiotrophoblast-derived extracellular vesicles (EVs), comprising microvesicles and exosomes, are released into the peripheral circulation in pregnancy and are postulated as a key mechanism coupling placental dysfunction and maternal phenotype in preeclampsia. We aimed to determine whether higher levels of active NEP are found in syncytiotrophoblast-derived EVs in preeclampsia compared with normal pregnancy. Using immunostaining and Western blotting, we first demonstrated that NEP levels are greater not only in preeclampsia placental tissue but also in syncytiotrophoblast-derived microvesicles and exosomes isolated from preeclampsia placentas ( P<0.05, n=5). We confirmed placental origin using antibody-coated magnetic beads to isolate NEP-bound vesicles, finding that they stain for placental alkaline phosphatase. NEP on syncytiotrophoblast-derived EVs is active and inhibited by thiorphan ( P<0.01, n=3; specific inhibitor). Syncytiotrophoblast-derived microvesicles, isolated from peripheral plasma, demonstrated higher NEP expression in preeclampsia using flow cytometry ( P<0.05, n=8). We isolated plasma exosomes using size-exclusion chromatography and showed greater NEP activity in preeclampsia ( P<0.05, n=8). These findings show that the placenta releases active NEP into the maternal circulation on syncytiotrophoblast-derived EVs, at significantly greater levels in preeclampsia. NEP has pathological roles in hypertension, heart failure, and amyloid deposition, all of which are features of preeclampsia. Circulating syncytiotrophoblast-derived EV-bound NEP thus may contribute to the pathogenesis of this disease.

Item Type:	Journal Article
Subjects:	R Medicine > RG Gynecology and obstetrics
Divisions:	Faculty of Medicine > Warwick Medical School > Biomedical Sciences Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Preeclampsia -- Risk factors -- Research, Hypertension in pregnancy, Pregnancy -- Complications, Placenta -- Physiology, Ribonucleases
Journal or Publication Title:	Hypertension
Publisher:	American Heart Association
ISSN:	0194-911X
Official Date:	1 May 2019
Dates:	Date Event 1 May 2019 Published 1 April 2019 Available 7 March 2019 Accepted
Date of first compliant deposit:	11 July 2019
Volume:	73
Number:	5
Page Range:	pp. 1112-1119
DOI:	10.1161/HYPERTENSIONAHA.119.12707
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Copyright Holders:	Manu Vatish
Related URLs:	Other Other Repository

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