CCL21/CCR7 Axis Contributes to Trophoblastic Cell Migration and Invasion in Preeclampsia by Affecting the Epithelial Mesenchymal Transition via the ERK1/2 Signaling Pathway

SIMPLE SUMMARY: Preeclampsia is a severe complication of human pregnancy. Despite intensive research efforts, effective treatment is still lacking. Impaired extravillous trophoblast invasion and incomplete spiral artery remodeling are thought to be the initial factors of PE. Furthermore, CCL21 has been widely reported to be associated with the metastasis of cancer cells. Considering the similarities between trophoblasts and cancer cells, we speculated that CCL21 might also affect trophoblast invasion and migration. In this study, we found the expression level of CCL21 was significantly lower in the PE group. In vitro study showed that CCL21 promoted trophoblast cell EMT processes and further enhanced its migration and invasion ability through the ERK1/2 signaling pathway. A mouse model of PE was established with L-NAME, and we obtained similar results. These data suggest that the CCL21/CCR7 axis affects EMT by activating the ERK1/2 signaling pathway, thereby affecting the migration and invasion of trophoblast cells. This contributes to effective therapeutic strategies for PE. ABSTRACT: Preeclampsia (PE) is a pregnancy-related disorder that is a leading cause of maternal death. The failure of spiral artery remodeling due to insufficient trophoblast migration and invasion is critical in the pathogenesis of PE. Recently, the CC motif chemokine ligand 21 (CCL21) has been widely linked to cancer cell invasion and migration. However, their potential mechanisms are still unknown. In this study, we found that CCL21 expression was significantly lower in the PE group than that in the control group. In vitro experiments revealed that recombinant CCL21 could promote trophoblast cell epithelial-to-mesenchymal transitions (EMTs) and improve migration and invasion. Furthermore, an inhibitor of the ERK1/2 signaling pathway inhibited the CCL21-induced EMT process. Finally, a PE mouse model was established using the NOS inhibitor L-NAME, and we obtained similar results, with downregulated CCL21 and EMT biomarkers and upregulated CCR7. Taken together, these findings suggest that the CCL21/CCR7 axis influences EMT by activating the ERK1/2 signaling pathway, thereby affecting trophoblast cell migration and invasion, which may play a crucial role in the pathogenesis of PE.