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-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.
Original language | English |
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Pages (from-to) | 399–412 |
Number of pages | 14 |
Journal | Hypertension |
Volume | 79 |
Issue number | 2 |
Early online date | 6 Dec 2021 |
DOIs | |
Publication status | Published - Feb 2022 |
Bibliographical note
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).
Publisher Copyright:
© 2021 American Heart Association, Inc.
Keywords
- Cytoskeleton
- Preeclampsia
- Pregnancy
- Sphingosine
- Trophoblasts
ASJC Scopus subject areas
- Internal Medicine