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

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

doi:10.1042/CS20210989

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

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^*

^*Corresponding author for this work

Internal Medicine

Research output: Contribution to journal › Article › Academic › peer-review

18 Citations (Scopus)

89 Downloads (Pure)

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.

Original language	English
Article number	10989
Pages (from-to)	257-272
Number of pages	16
Journal	Clinical science (London, England : 1979)
Volume	136
Issue number	4
DOIs	https://doi.org/10.1042/CS20210989
Publication status	Published - 25 Feb 2022

Bibliographical note

Funding Information:
This work was supported by the National Natural Science Foundation of China [grant numbers 81830041, 81771617, 81771611, 31572591]; the Shenzhen Basic Research Fund [grant numbers JCYJ20170413165233512, JCYJ20170412140326739]; the Guangdong Provincial Science and Technology Program [grant number 2019B030301009]; and the Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis [grant number ZDSYS20190902092903237].

Publisher Copyright:
© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Access to Document

10.1042/CS20210989Licence: CC BY-NC-ND

Placental trophoblast-specific overexpression ofFinal published version, 5.28 MBLicence: CC BY-NC-ND

Cite this

Tan, L., Chen, Z., Sun, F., Zhou, Z., Zhang, B., Wang, B., Chen, J., Li, M., Xiao, T., Neuman, R. I., Niu, J., Verdonk, K., Lu, X., Zhang, J. V., Danser, A. H. J., Yang, Q., & Fan, X. (2022). Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms. Clinical science (London, England : 1979), 136(4), 257-272. Article 10989. https://doi.org/10.1042/CS20210989

@article{2e3474b2c27a42cf8aa81bdee7dbc6a0,

title = "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.",

author = "Lunbo Tan and Zhilong Chen and Fen Sun and Zhuoqun Zhou and Baozhen Zhang and Baobei Wang and Jie Chen and Mengxia Li and Tianxia Xiao and Neuman, {Rugina I.} and Jianmin Niu and Koen Verdonk and Xifeng Lu and Zhang, {Jian V.} and Danser, {A. H.Jan} and Qing Yang and Xiujun Fan",

note = "Funding Information: This work was supported by the National Natural Science Foundation of China [grant numbers 81830041, 81771617, 81771611, 31572591]; the Shenzhen Basic Research Fund [grant numbers JCYJ20170413165233512, JCYJ20170412140326739]; the Guangdong Provincial Science and Technology Program [grant number 2019B030301009]; and the Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis [grant number ZDSYS20190902092903237]. Publisher Copyright: {\textcopyright} 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.",

year = "2022",

month = feb,

day = "25",

doi = "10.1042/CS20210989",

language = "English",

volume = "136",

pages = "257--272",

journal = "Clinical science (London, England : 1979)",

issn = "0143-5221",

publisher = "Portland Press, Ltd.",

number = "4",

}

Tan, L, Chen, Z, Sun, F, Zhou, Z, Zhang, B, Wang, B, Chen, J, Li, M, Xiao, T, Neuman, RI, Niu, J, Verdonk, K, Lu, X, Zhang, JV, Danser, AHJ, Yang, Q & Fan, X 2022, 'Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms', Clinical science (London, England : 1979), vol. 136, no. 4, 10989, pp. 257-272. https://doi.org/10.1042/CS20210989

TY - JOUR

T1 - Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms

AU - Tan, Lunbo

AU - Chen, Zhilong

AU - Sun, Fen

AU - Zhou, Zhuoqun

AU - Zhang, Baozhen

AU - Wang, Baobei

AU - Chen, Jie

AU - Li, Mengxia

AU - Xiao, Tianxia

AU - Neuman, Rugina I.

AU - Niu, Jianmin

AU - Verdonk, Koen

AU - Lu, Xifeng

AU - Zhang, Jian V.

AU - Danser, A. H.Jan

AU - Yang, Qing

AU - Fan, Xiujun

N1 - Funding Information: This work was supported by the National Natural Science Foundation of China [grant numbers 81830041, 81771617, 81771611, 31572591]; the Shenzhen Basic Research Fund [grant numbers JCYJ20170413165233512, JCYJ20170412140326739]; the Guangdong Provincial Science and Technology Program [grant number 2019B030301009]; and the Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis [grant number ZDSYS20190902092903237]. Publisher Copyright: © 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

PY - 2022/2/25

Y1 - 2022/2/25

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85124577260&partnerID=8YFLogxK

U2 - 10.1042/CS20210989

DO - 10.1042/CS20210989

M3 - Article

C2 - 35103285

AN - SCOPUS:85124577260

SN - 0143-5221

VL - 136

SP - 257

EP - 272

JO - Clinical science (London, England : 1979)

JF - Clinical science (London, England : 1979)

IS - 4

M1 - 10989

ER -

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

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this