Placenta · 2026
Impaired syncytin-1-CXCR4 crosstalk contributes to trophoblast migration defects in preeclampsia.
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Wang Ya-Nan, Zhang Hai-Feng, Chen Xue-Ling, Yang Ju, Xue Yun-Shan, Chen Pei-Shan, Chen Hai-Bin
Аннотация
BACKGROUND: Preeclampsia is a pregnancy-specific disorder characterized by de novo hypertension and proteinuria after 20 weeks of gestation, affecting 3-8% of pregnant women globally. Current management relies primarily on preventive strategies and symptomatic relief, with urgent delivery remaining the only definitive intervention. Syncytin-1, a human endogenous retroviral envelope protein, is implicated in preeclampsia pathogenesis via modulating trophoblast function and uterine spiral artery remodeling, though its precise molecular mechanisms remain unclear.
METHODS: This study utilized transcriptome sequencing of syncytin-a conditional knockout mice, alongside String database analysis, ClusPro/GRAMM/HDOCK molecular docking, immunofluorescence co-localization, and co-immunoprecipitation to predict and validate Syncytin-1 interacting partners. Bioinformatics, western blotting, and RT-qPCR were applied to screen and confirm differentially expressed genes in preeclamptic cell models and placental tissues. HTR-8/SVneo cells were treated with si-ERVW-1, the CXCR4 inhibitor AMD3100, or the CXCR4 agonist NUCC390, followed by functional analyses.
RESULTS: We identified direct co-localization and interaction between Syncytin-1 and CXCR4 in HTR-8/SVneo cells. Downregulated expression of Syncytin-1 and key components of the CXCR4/GNAQ/CALM2/NFATC1 pathway was observed in preeclamptic cell models and placental tissues. In HTR-8/SVneo cells, si-ERVW-1 or AMD3100 treatment markedly reduced Syncytin-1 and CXCR4 signaling molecule expression (CXCR4, GNAQ, CALM2, NFATC1) and significantly suppressed cell migration and invasion effects reversed by NUCC390.
CONCLUSION: These findings suggest that Syncytin-1 downregulation may drive preeclampsia by targeting CXCR4 to inhibit the GNAQ/CALM2/NFATC1 pathway and reduce trophoblast migratory and invasive capacities.
METHODS: This study utilized transcriptome sequencing of syncytin-a conditional knockout mice, alongside String database analysis, ClusPro/GRAMM/HDOCK molecular docking, immunofluorescence co-localization, and co-immunoprecipitation to predict and validate Syncytin-1 interacting partners. Bioinformatics, western blotting, and RT-qPCR were applied to screen and confirm differentially expressed genes in preeclamptic cell models and placental tissues. HTR-8/SVneo cells were treated with si-ERVW-1, the CXCR4 inhibitor AMD3100, or the CXCR4 agonist NUCC390, followed by functional analyses.
RESULTS: We identified direct co-localization and interaction between Syncytin-1 and CXCR4 in HTR-8/SVneo cells. Downregulated expression of Syncytin-1 and key components of the CXCR4/GNAQ/CALM2/NFATC1 pathway was observed in preeclamptic cell models and placental tissues. In HTR-8/SVneo cells, si-ERVW-1 or AMD3100 treatment markedly reduced Syncytin-1 and CXCR4 signaling molecule expression (CXCR4, GNAQ, CALM2, NFATC1) and significantly suppressed cell migration and invasion effects reversed by NUCC390.
CONCLUSION: These findings suggest that Syncytin-1 downregulation may drive preeclampsia by targeting CXCR4 to inhibit the GNAQ/CALM2/NFATC1 pathway and reduce trophoblast migratory and invasive capacities.