Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms.

Abstract

Maternal circulating levels of the adipokine chemerin are elevated in preeclampsia, but its origin and contribution to preeclampsia remain unknown. We therefore studied (1) placental chemerin expression and release in human pregnancy, and (2) the consequences of chemerin overexpression via lentivirus-mediated trophoblast-specific gene manipulation in both mice and immortalized human trophoblasts. Placental chemerin expression and release were increased in women with preeclampsia, and their circulating chemerin levels correlated positively with the soluble Fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, a well-known biomarker of preeclampsia severity. Placental trophoblast chemerin overexpression in mice induced a preeclampsia-like syndrome, involving hypertension, proteinuria, and endotheliosis, combined with diminished trophoblast invasion, a disorganized labyrinth layer, and up-regulation of sFlt-1 and the inflammation markers nuclear factor-κB (NFκB), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. It also led to embryo resorption, while maternal serum chemerin levels correlated negatively with fetal weight in mice. Chemerin overexpression in human trophoblasts up-regulated sFlt-1, reduced vascular endothelial factor-A, and inhibited migration and invasion, as well as tube formation during co-culture with human umbilical vein endothelial cells (HUVECs). The chemokine-like receptor 1 (CMKLR1) antagonist α-NETA prevented the latter phenomenon, although it did not reverse the chemerin-induced down-regulation of the phosphoinositide 3-kinase/Akt pathway. In conclusion, up-regulation of placental chemerin synthesis disturbs normal placental development via its CMKLR1 receptor, thereby contributing to fetal growth restriction/resorption and the development of preeclampsia. Chemerin might be a novel biomarker of preeclampsia, and inhibition of the chemerin/CMKLR1 pathway is a promising novel therapeutic strategy to treat preeclampsia.

• Authors: Lunbo Tan, Zhilong Chen, Fen Sun, Zhuoqun Zhou, Baozhen Zhang, Baobei Wang, Jie Chen, Mengxia Li, Tianxia Xiao, Rugina I Neuman, Jianmin Niu, Koen Verdonk, Xifeng Lu, Jian V Zhang, A H Jan Danser, Qing Yang, Xiujun Fan
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 136 Issue 4 Pg. 257-272 (02 25 2022) ISSN: 1470-8736 [Electronic] England
• PMID: 35103285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Author(s).

Chemical References

• Chemokines
• Intercellular Signaling Peptides and Proteins
• RARRES2 protein, human
• chemerin protein, mouse
• Placenta Growth Factor
• FLT1 protein, human
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Cell Line
• Chemokines (genetics, metabolism)
• Female
• Human Umbilical Vein Endothelial Cells
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Mice
• Placenta (metabolism, pathology)
• Placenta Growth Factor (metabolism)
• Pre-Eclampsia (etiology)
• Pregnancy
• Pregnancy Outcome
• Trophoblasts (metabolism, pathology)
• Vascular Endothelial Growth Factor Receptor-1 (metabolism)