The cadherin superfamily in pregnancy disorders: from maternal–fetal interface biology to translational opportunities

Successful pregnancy depends on coordinated cell adhesion, trophoblast differentiation, vascular remodeling, and immune adaptation at the maternal–fetal interface. Cadherins couple intercellular adhesion to cytoskeletal dynamics and intracellular signaling, linking tissue integrity with placental development and the local immune microenvironment. This review integrates human tissue and circulating biomarker studies with experimental evidence, using selected single-cell and spatial studies to contextualize cadherin expression across cell states and tissue compartments in pregnancy. Spatiotemporal regulation of E-cadherin, N-cadherin, and vascular endothelial cadherin supports trophoblast epithelial–mesenchymal plasticity, controlled invasion, and trophoblast–endothelial interactions involved in spiral artery remodeling. Cadherin–catenin complexes connect these processes to Wnt/β-catenin signaling and extracellular matrix remodeling, while altered endothelial junctions may compromise vascular barrier integrity. At the intersection of adhesion and immune regulation, cadherin-dependent tissue organization may influence decidual–trophoblast communication and the cellular context supporting maternal–fetal immune tolerance. Conversely, immune-cell-derived inflammatory signals can disrupt cadherin-mediated adhesion. In fetal membranes, macrophage-derived extracellular vesicles promote E-cadherin loss and epithelial–mesenchymal transition, illustrating how immune-cell–epithelial crosstalk can contribute to membrane weakening. These interconnected processes provide a framework for understanding implantation failure, recurrent pregnancy loss, preeclampsia, fetal growth restriction, preterm birth and membrane rupture, and abnormal placentation. We critically distinguish disease-associated findings from causal mechanisms, with particular attention to the limited direct evidence linking cadherins to immune tolerance. Integrating cadherin-related adhesion, vascular, and immune signatures may inform biomarker development and risk stratification and guide investigation of targeted interventions; however, functional validation and prospective clinical studies remain essential.