Beyond Neurobiology: Cellular Prion Protein (PRNP) as an Emerging Regulator of Decidual and Utero-Placental Vascular Function

Abstract The establishment of a functional utero-placental interface depends on the precise temporal and spatial coordination of blastocyst attachment, decidual transformation, trophoblast invasion, and uterine spiral artery remodelling (SAR). Disruption of these tightly regulated processes underlies major placental pathologies, including preeclampsia, fetal growth restriction, and stillbirth. Although significant advances have been made in defining the molecular networks governing placental development, the contribution of cellular prion protein (PRNP) remains poorly characterized. warranting a focused review. Classically studied in the context of neurobiology and prion-associated neurodegenerative diseases, PRNP is now emerging as an important regulator of reproductive and vascular physiology. This review provides an overview of current evidence supporting non-neuronal roles of PRNP during early pregnancy, with particular emphasis on decidualization and utero-placental vascular adaptation. PRNP displays dynamic expression in the uterine glands, decidua, and vascular smooth muscle cells (VSMCs), where it contributes to tight-junction integrity, decidual cell survival, and autophagic homeostasis. Within the vascular compartment, PRNP regulates trophoblast-directed VSMC phenotypic switching by limiting proliferation, promoting platelet-derived growth factor-β-focal adhesion kinase (PDGFR-β-FAK) -dependent migration, and protecting VSMCs from TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, processes essential for effective SAR. Notably, PRNP expression is transcriptionally regulated by odd-skipped related 1 (OSR1), which is itself negatively modulated by trophoblast cells. Collectively, these findings position PRNP beyond its traditional neurobiological role as a sensitive molecular indicator of decidual competence and vascular remodelling status, highlighting its potential as a biomarker and therapeutic target in placental disorders.