Impaired sphingosine-1-phosphate synthesis induces preeclampsia by deactivating trophoblastic YAP (Yes-associated protein) through S1PR2 (sphingosine-1-phosphate receptor-2)-induced actin polymerizations

Liao, Jiujiang, Zheng, Yangxi, Hu, Mingyu, Xu, Ping, Lin, Li, Liu, Xiyao, Wu, Yue, Huang, Biao, Ye, Xuan, Li, Sisi, Duan, Ran, Fu, Huijia, Huang, Jiayu, Wen, Li, Fu, Yong, Kilby, Mark D., Kenny, Louise C., Baker, Philip N., Qi, Hongbo and Tong, Chao (2022) Impaired sphingosine-1-phosphate synthesis induces preeclampsia by deactivating trophoblastic YAP (Yes-associated protein) through S1PR2 (sphingosine-1-phosphate receptor-2)-induced actin polymerizations. Hypertension, 79 (2). pp. 399-412. ISSN 0194-911X

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Abstract

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-1phosphate 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-1phosphate 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.

Item Type:	Article
Additional Information:	Funding information: This study was funded by National Key R&D Program of China (2018YFC1004103), National Natural Science Foundation of China (81671488, 81771613, 81871189, and 82071675).
Uncontrolled Keywords:	cytoskeleton,preeclampsia,pregnancy,sphingosine,trophoblasts,internal medicine,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2724
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	30 May 2025 14:30
Last Modified:	30 May 2025 14:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99361
DOI:	10.1161/HYPERTENSIONAHA.121.18363

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