Antiphospholipid syndrome (APS) is associated with recurrent pregnancy morbidity, yet the underlying mechanisms remain elusive. We performed multifaceted characterization of the biological and transcriptomic signatures of mouse placenta and uterine natural killer (uNK) cells in APS. Histological analysis of APS placentas unveiled placental abnormalities, including disturbed angiogenesis, occasional necrotic areas, fibrin deposition, and nucleated red blood cell enrichment. Analyses of APS placentas showed a reduced cell proliferation, lower protein content and thinning of endothelial cells. Disturbances in APS trophoblast cells were linked to a cell cycle shift in cytotrophoblast cells, and a reduced number of spiral artery-associated trophoblast giant cells (SpA-TGC). Transcriptomic profiling of placental tissue highlighted disruptions in cell cycle regulation with notable downregulation of genes involved in developmental or signaling processes. Cellular senescence, metabolic and p53-related pathways were also enriched, suggesting potential mechanisms underlying placental dysfunction in APS. Thrombotic events, though occasionally detected, appeared to have no significant impact on the overall pathological changes. The increased number of dysfunctional uNK cells was not associated with enhanced cytotoxic capabilities. Transcriptomic data corroborated these findings, showing prominent suppression of NK cell secretory capacity and cytokine signaling pathways. Our study highlights the multifactorial nature of APS-associated placental pathologies, which involve disrupted angiogenesis, cell cycle regulation, and NK cell functionality.

Department of Clinical and Molecular Pathology Faculty of Medicine and Dentistry Palacký University Olomouc and University Hospital Olomouc Olomouc Czech Republic

Department of Computer Science Faculty of Electrical Engineering and Computer Science VSB Technical University of Ostrava Ostrava Czech Republic

Department of Immunology Faculty of Medicine and Dentistry Palacký University Olomouc and University Hospital Olomouc Olomouc Czech Republic

Laboratory of Cell Biology and Virology Institute of Molecular Biology of NAS RA Yerevan 0014 Armenia

Laboratory of Molecular and Cellular Immunology Institute of Molecular Biology NAS RA 7 Hasratyan Str Yerevan 0014 Armenia

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NK cell dysfunction in antiphospholipid syndrome