Impaired placental vascular remodeling and persistent uNK cells in the RUPP model: A time-dependent perspective

Background: Placental insufficiency underlies major obstetric complications such as preeclampsia and fetal growth restriction (FGR). The reduced uterine perfusion pressure (RUPP) model is widely used to mimic PE and FGR; however, its impact on placental structure, immune cell regulation, and vascular remodeling in the mesometrial triangle remains poorly examined. This study investigates these processes to clarify the model's relevance for human placenta dysfunction pathology. Methods: Maternal, fetal, and placental parameters were assessed in pregnant rats at gestational day (GD) 14, 16, 18, and 19, comparing normal pregnant and RUPP groups. Placental morphology was assessed using hematoxylin and eosin staining. Within the mesometrial triangle, uterine natural killer (uNK) cell distribution was evaluated using ANK61 staining, while trophoblast invasion and spiral artery remodeling were assessed by pan-cytokeratin and α-SMA staining, respectively. Results: Placental macrostructural architecture was preserved in RUPP. However, uNK cell migration from the mesometrial triangle was impaired, with higher ANK61-positive cell presence persisting at GD19. This was accompanied by a reduction in trophoblast invasion depth. Spiral artery remodeling was impaired in RUPP placentas, with a greater proportion of unremodeled vessels and fewer highly remodeled arteries by GD19. Conclusion: While gross placental structure remains intact in the RUPP model, the key functional adaptations uNK cell migration, trophoblast invasion, and vascular remodeling, are impaired. These findings support the RUPP as a relevant model to study the pathophysiological mechanisms of placental insufficiency. Future research should focus on temporal molecular profiling to elucidate the mechanisms behind impaired uNK cell retention and shallow trophoblast invasion.