Cold stress exacerbates preeclampsia pathogenesis by upregulating Map7 expression in placental macrophages

Preeclampsia (PE) is a severe hypertension-related complication of pregnancy, driven by crosstalk between environmental exposures and genetic susceptibility. Cold exposure is recognized as a risk factor for PE, yet its underlying molecular mechanisms remain unclear. This study aimed to determine whether cold stress exacerbates PE-like phenotypes and clarify the pathogenic function of placental Map7.

Pregnant mice were subjected to an L-NAME-induced PE-like model with or without chronic cold exposure. Maternal phenotypes, placental pathology, inflammation, and angiogenic balance were evaluated. Proteomics and immunofluorescence were used to identify and localize placental candidate proteins. In vitro macrophage manipulation and conditioned medium assays evaluated Map7's effects on macrophage polarization and trophoblast function.

Cold exposure markedly worsened PE-like manifestations, including hypertension, proteinuria, fetal growth restriction, and placental injury. Proteomics identified Map7 as progressively upregulated from controls to PE-like mice, and further in cold-exposed PE-like mice, prominently localizing in placental macrophages. MAP7 overexpression promoted M1-like macrophage polarization and inflammatory cytokine production via activating the NF-κB signaling pathway, whereas MAP7 knockdown attenuated these effects. Furthermore, conditioned medium from Map7-overexpressing macrophages impaired trophoblast proliferation, migration, invasion, and angiogenesis, which was reversed by MAP7 silencing.

Map7 mediates the cold stress-aggravated PE-like phenotype. Targeting the macrophage-associated Map7/NF-κB axis represents a potential therapeutic strategy for environmentally triggered placental immune dysfunction.