Xirong Xiao1, Fengyi Xiao1, Mingzhi Zhao1, Mancy Tong2, Michelle R Wise2, Peter R Stone2, Lawrence W Chamley2, Qi Chen3. 1. The Hospital of Obstetrics & Gynaecology, Fudan University, China; Department of Obstetrics & Gynaecology, The University of Auckland, New Zealand. 2. Department of Obstetrics & Gynaecology, The University of Auckland, New Zealand. 3. The Hospital of Obstetrics & Gynaecology, Fudan University, China; Department of Obstetrics & Gynaecology, The University of Auckland, New Zealand. Electronic address: q.chen@auckland.ac.nz.
Abstract
OBJECTIVES: Preeclampsia is characterised by systemic endothelial cell dysfunction thought to be triggered by toxic/dangerous factors from the placenta, including placental extracellular vesicles (EVs). Why placental EVs become toxic is unknown. We previously reported that preeclamptic sera produced toxic/dangerous placental macrovesicles but whether small EVs are also toxic/dangerous in preeclampsia is unknown. STUDY DESIGN: First trimester placental explants were treated with 10% preeclamptic or control sera (n=10) for 24h. Micro- and nano-vesicles were harvested by sequential centrifugation. Micro- or nano-vesicles were also exposed to monolayers of endothelial cells in the presence or absence of nifedipine (50μg/ml) or labetalol (0.5μg/ml) which are well-known anti-hypertensives in clinical practices. MAIN OUTCOMES MEASURES: The number and size of micro- and nano-vesicles were counted. Endothelial cell-surface intercellular adhesion molecule 1 (ICAM-1) and high mobility group box 1 (HMGB1) levels in micro- or nano-vesicles were measured by immunoassays. RESULTS: Neither the amount nor size of both micro- and nano-vesicles was different after treating placental explants with preeclamptic or control sera. The levels of HMGB1 were significantly increased in both micro- and nano-vesicles from preeclamptic sera treated placental explants (p<0.03). Exposing endothelial cells to micro- or nano-vesicles from preeclamptic sera-treated placental explants induced endothelial activation, but it was reversed by co-incubation with nifedipine (p=0.004) or labetalol (p=0.002). CONCLUSION: Our data demonstrate that preeclamptic sera produce toxic/dangerous micro- and nano-placental EVs which activated endothelial cells. This effect was reversed by antihypertensives. The increased levels of HMGB1 in EVs may contribute to endothelial cell activation.
OBJECTIVES: Preeclampsia is characterised by systemic endothelial cell dysfunction thought to be triggered by toxic/dangerous factors from the placenta, including placental extracellular vesicles (EVs). Why placental EVs become toxic is unknown. We previously reported that preeclamptic sera produced toxic/dangerous placental macrovesicles but whether small EVs are also toxic/dangerous in preeclampsia is unknown. STUDY DESIGN: First trimester placental explants were treated with 10% preeclamptic or control sera (n=10) for 24h. Micro- and nano-vesicles were harvested by sequential centrifugation. Micro- or nano-vesicles were also exposed to monolayers of endothelial cells in the presence or absence of nifedipine (50μg/ml) or labetalol (0.5μg/ml) which are well-known anti-hypertensives in clinical practices. MAIN OUTCOMES MEASURES: The number and size of micro- and nano-vesicles were counted. Endothelial cell-surface intercellular adhesion molecule 1 (ICAM-1) and high mobility group box 1 (HMGB1) levels in micro- or nano-vesicles were measured by immunoassays. RESULTS: Neither the amount nor size of both micro- and nano-vesicles was different after treating placental explants with preeclamptic or control sera. The levels of HMGB1 were significantly increased in both micro- and nano-vesicles from preeclamptic sera treated placental explants (p<0.03). Exposing endothelial cells to micro- or nano-vesicles from preeclamptic sera-treated placental explants induced endothelial activation, but it was reversed by co-incubation with nifedipine (p=0.004) or labetalol (p=0.002). CONCLUSION: Our data demonstrate that preeclamptic sera produce toxic/dangerous micro- and nano-placental EVs which activated endothelial cells. This effect was reversed by antihypertensives. The increased levels of HMGB1 in EVs may contribute to endothelial cell activation.
Authors: Daniela Cesselli; Pietro Parisse; Aneta Aleksova; Claudia Veneziano; Celeste Cervellin; Andrea Zanello; Antonio Paolo Beltrami Journal: Front Physiol Date: 2018-10-01 Impact factor: 4.566
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