Page 228 - Haematologica - Vol. 105 n. 6 - June 2020

Hemostasis
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1686-1694
Placenta-derived extracellular vesicles induce preeclampsia in mouse models
Cha Han,1,2* Chenyu Wang,3* Yuanyuan Chen,1 Jiwei Wang,4 Xin Xu,2 Tristan Hilton,2 Wei Cai,3 Zilong Zhao,5 Yingang Wu,6 Ke Li,1 Katie Houck,2 Li Liu,5 Anil K. Sood,7 Xiaoping Wu,2 Fengxia Xue,1 Min Li,3* Jing-fei Dong2,8 and Jianning Zhang5
1Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin, China; 2Bloodworks Research Institute, Seattle, WA, USA; 3 Institute of Pathology, School of Medical Sciences and Gansu Provincial Key Laboratory of Preclinical Study for New Drug Development, Lanzhou University, Lanzhou, China; 4Department of Neurosurgery, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Huanhu Hospital, Tianjin, China; 5Department of Neurosurgery, Tianjin Medical University General Hospital and Tianjin Neurological Institute, Tianjin, China; 6Department of Neurosurgery, the First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; 7Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, MD Anderson Cancer Center, University of Texas, Houston, TX, USA and 8Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA, USA.
*CH and CW contributed equally as co-first author.
ABSTRACT
Preeclampsia is a pregnancy-induced condition that impairs the mother’s health and results in pregnancy termination or premature delivery. Elevated levels of placenta-derived extracellular vesicles (pcEV) in the circulation have been consistently associated with preeclampsia, but whether these vesicles induce preeclampsia or are the product of preeclampsia is not known. Guided by a small cohort study of preeclamptic patients, we examined the impact of pcEV on the patho- genesis of preeclampsia in mouse models. We detected pcEV in pregnant C56BL/6J mice with a peak level of 3.8±0.9×107/mL at 17-18 days post- coitum. However, these pregnant mice developed hypertension and pro- teinuria only after being infused with vesicles purified from injured pla- centa. These extracellular vesicles released from injured placenta disrupt- ed endothelial integrity and induced vasoconstriction. Enhancing the clearance of extracellular vesicles prevented the development of the extracellular vesicle-induced preeclampsia in mice. Our results demon- strate a causal role of pcEV in preeclampsia and identify microvesicle clearance as a new therapeutic strategy for the treatment of this pregnan- cy-associated complication.
Introduction
Preeclampsia is a pregnancy-induced pathology characterized by poor placenta- tion and endothelial dysfunction. Its primary clinical presentations include new- onset hypertension and proteinuria that resolve or are significantly improved after delivery or pregnancy termination.1,2 Preeclampsia can progress into eclampsia, potentially resulting in maternal and fetal death. Extensive clinical and laboratory studies have demonstrated that preeclampsia is triggered by placenta-derived medi- ators3 produced after placental ischemia and reperfusion injury, which could result from placental spiral artery remodeling disorders.4,5 One of these mediators is pla- centa-derived extracellular vesicles (pcEV), which are released into the maternal cir- culation, typically reaching a peak level in late pregnancy.6-8 These pcEV are consti- tutively released during normal pregnancy and are necessary for inducing maternal adaptive changes such as tolerance.9 However, excessive shedding of pcEV often indicates placental pathologies that contribute to the pathogenesis of preeclampsia.
Correspondence:
MIN LI
limin@lzu.edu.cn
JIANNING ZHANG
jianningzhang@hotmail.com
JING-FEI DONG
jfdong@bloodworksnw.org
Received: May 6, 2019. Accepted: August 22, 2019. Pre-published: August 22, 2019.
doi:10.3324/haematol.2019.226209
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/6/1686
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