Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
College of Veterinary Medicine, Hunan Agricultural University, Changsha, Hunan 410128, China.
Clin Sci (Lond). 2022 Feb 25;136(4):257-272. doi: 10.1042/CS20210989.
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.
母体循环中的脂肪因子趋化素在子痫前期中升高，但它的来源及其对子痫前期的贡献尚不清楚。因此，我们研究了（1）人类妊娠中胎盘趋化素的表达和释放，以及（2）通过慢病毒介导的滋养层特异性基因操作过表达趋化素对小鼠和永生化人滋养层的影响。子痫前期妇女的胎盘趋化素表达和释放增加，其循环趋化素水平与可溶性 Fms 样酪氨酸激酶-1（sFlt-1）/胎盘生长因子（PlGF）比值呈正相关，这是子痫前期严重程度的一个众所周知的生物标志物。在小鼠中过表达胎盘滋养层趋化素会诱导子痫前期样综合征，包括高血压、蛋白尿和内皮细胞病，同时伴有滋养层侵袭减少、迷宫层结构紊乱以及 sFlt-1 和炎症标志物核因子-κB（NFκB）、肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β的上调。它还导致胚胎吸收，而母鼠血清趋化素水平与胎儿体重呈负相关。在人滋养层中过表达趋化素会上调 sFlt-1，降低血管内皮生长因子-A，并抑制迁移和侵袭，以及与脐静脉内皮细胞（HUVECs）共培养时的管形成。趋化因子样受体 1（CMKLR1）拮抗剂 α-NETA 可预防后一种现象，但不能逆转趋化素诱导的磷酸肌醇 3-激酶/Akt 通路下调。总之，胎盘趋化素合成的上调通过其 CMKLR1 受体扰乱正常胎盘发育，从而导致胎儿生长受限/吸收和子痫前期的发生。趋化素可能是子痫前期的一个新的生物标志物，抑制趋化素/CMKLR1 途径是治疗子痫前期的一种有前途的新的治疗策略。
