Academic Journal
Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations.
| Title: | Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations. |
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| Authors: | Liao J; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Zheng Y; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX (Y.Z.)., Hu M; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Xu P; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Lin L; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Liu X; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Wu Y; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Huang B; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Ye X; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Li S; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Duan R; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Fu H; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Huang J; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Wen L; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Fu Y; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.)., Kilby MD; Institute of Metabolism and System Research, College of Medical & Dental Sciences, University of Birmingham and the Fetal Medicine Centre, Birmingham Women's and Children's Foundation Trust, United Kingdom (M.D.K.)., Kenny LC; Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, United Kingdom (L.C.K.)., Baker PN; College of Life Sciences, University of Leicester, United Kingdom (P.N.B.)., Qi H; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; Chongqing Women and Children's Health Center, China (H.Q.)., Tong C; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (J.L., Y.Z., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.).; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, China (J.L., M.H., P.X., L.L., X.L., Y.W., B.H., X.Y., S.L., R.D., H.F., J.H., L.W., Y.F., H.Q., C.T.). |
| Source: | Hypertension (Dallas, Tex. : 1979) [Hypertension] 2022 Feb; Vol. 79 (2), pp. 399-412. Date of Electronic Publication: 2021 Dec 06. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Lippincott, Williams & Wilkins Country of Publication: United States NLM ID: 7906255 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4563 (Electronic) Linking ISSN: 0194911X NLM ISO Abbreviation: Hypertension Subsets: MEDLINE |
| Imprint Name(s): | Publication: Original Publication: [Dallas, Tex.] : [American Heart Association], [©1979]- |
| MeSH Terms: | Actins/*metabolism , Lysophospholipids/*metabolism , Pre-Eclampsia/*metabolism , Proto-Oncogene Proteins c-yes/*metabolism , Sphingosine/*analogs & derivatives , Sphingosine-1-Phosphate Receptors/*metabolism , Trophoblasts/*metabolism, Lysophospholipids/genetics ; Placenta/metabolism ; Placentation/physiology ; Proto-Oncogene Proteins c-yes/genetics ; Signal Transduction/physiology ; Sphingosine/genetics ; Sphingosine/metabolism ; Sphingosine-1-Phosphate Receptors/genetics ; Animals ; Female ; Humans ; Mice ; Pregnancy |
| 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. |
| Contributed Indexing: | Keywords: cytoskeleton; preeclampsia; pregnancy; sphingosine; trophoblasts |
| Substance Nomenclature: | 0 (Actins) 0 (Lysophospholipids) 0 (Sphingosine-1-Phosphate Receptors) 0 (sphingosine-1-phosphate receptor-2, mouse) 26993-30-6 (sphingosine 1-phosphate) EC 2.7.10.2 (Proto-Oncogene Proteins c-yes) EC 2.7.10.2 (Yes1 protein, mouse) NGZ37HRE42 (Sphingosine) |
| Entry Date(s): | Date Created: 20211206 Date Completed: 20220228 Latest Revision: 20220228 |
| Update Code: | 20260130 |
| DOI: | 10.1161/HYPERTENSIONAHA.121.18363 |
| PMID: | 34865521 |
| Database: | MEDLINE |
| ISSN: | 1524-4563 |
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| DOI: | 10.1161/HYPERTENSIONAHA.121.18363 |