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 trophoblast. 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 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 upregulation of sFlt-1 and the inflammation markers nuclear factor-kappa B, tumor necrosis factor-α and interleukin-1β. It also led to embryo resorption, while maternal serum chemerin levels correlated negatively with fetal weight in mice. Chemerin overexpression in human trophoblasts upregulated 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. The chemokine-like receptor 1 (CMKLR1) antagonist α-NETA prevented the latter phenomena, although it did not reverse the chemerin-induced downregulation of the phosphoinositide 3-kinase/Akt pathway. In conclusion, upregulation 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.

The Regulatory Roles of Chemerin-Chemokine-Like Receptor 1 Axis in Placental Development and Vascular Remodeling During Early Pregnancy

“…Patients suffering from hypertension and PE showed significantly higher serum chemerin concentrations ( Cetin et al, 2017 ; Xie and Liu, 2022 ). The increased placental chemerin was also found in the villi of preeclamptic women ( Xu et al, 2014 ; Tan et al, 2022 ). Our findings demonstrated that Cmklr1 knockout mice had more invaded trophoblasts and larger arteries in the decidua and myometrium than those in wildtype mice.…”

“…Our findings demonstrated that Cmklr1 knockout mice had more invaded trophoblasts and larger arteries in the decidua and myometrium than those in wildtype mice. Consistently, overexpression of trophoblastic chemerin diminishes trophoblast invasion ( Tan et al, 2022 ). These observations indicate that CMKLR1 mediates the role of chemerin in pregnancy.…”

“…The increased placental chemerin level was related to human PE and overexpression of chemerin in trophoblast contributed to the development of PE-like symptoms via its receptor CMKLR1 ( Tan et al, 2022 ). Here, to elucidate the role of chemerin-CMKLR1 in pregnancy, we generated mice knockout for Cmklr1 .…”

Chemerin Effect on the Endometrial Proteome of the Domestic Pig during Implantation Obtained by LC-MS/MS Analysis

“…Recent reports confirmed the role of CHEM in the pathogenesis of preeclampsia. Tan et al [ 75 ] indicated that placental CHEM expression and release increased in women with this disorder. It has been shown that CHEM reduced vascular endothelial factor-A and inhibited trophoblast migration and invasion.…”

“…It has been shown that CHEM reduced vascular endothelial factor-A and inhibited trophoblast migration and invasion. Moreover, according to the same authors, trophoblast CHEM overexpression in mice contributed to fetal growth restriction [ 75 ]. In the present study, CHEM, by increasing the expression of TGFβ1 protein in the endometrium, may contribute to the inadequate activation of NK cells and the development of preeclampsia.…”