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Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations

journal contribution
posted on 2022-02-22, 16:29 authored by Jiujiang Liao, Yangxi Zheng, Mingyu Hu, Ping Xu, Li Lin, Xiyao Liu, Yue Wu, Biao Huang, Xuan Ye, Sisi Li, Ran Duan, Huijia Fu, Jiayu Huang, Li Wen, Yong Fu, Mark D Kilby, Louise C Kenny, Philip N Baker, Hongbo Qi, Chao Tong
Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized human trophoblst cells) cell invasion in a Hippo-signaling-dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA (Ras homolog gene family, member A)/ROCK (Rho-associated protein kinase) induced actin polymerization. Mutation-based YAP-5SA (S61A, S109A, S127A, S164A, S381A) demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

Funding

National Key R&D Program of China (2018YFC1004103)

National Natural Science Foundation of China (81671488, 81771613, 81871189, and 82071675)

History

Citation

Hypertension. 2022;79:399–412. https://doi.org/10.1161/HYPERTENSIONAHA.121.18363

Author affiliation

College of Life Sciences, University of Leicester

Version

  • AM (Accepted Manuscript)

Published in

Hypertension

Volume

79

Issue

2

Pagination

399 - 412

Publisher

Lippincott, Williams & Wilkins

issn

0194-911X

eissn

1524-4563

Acceptance date

2022-11-22

Copyright date

2021

Available date

2022-06-06

Language

English