Differential Activation of p53‐Lamin A/C and p16‐ <scp>Rb</scp> ‐Mediated Senescence Pathways in Trophoblasts From Pregnancies Complicated by Type <scp>A2</scp> Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) increases the risks for fetal complications such as large-for-gestational-age infants and stillbirth, and disposes both the mother and fetus to develop type 2 diabetes in later life. The placenta, which is crucial for fetal development, exhibits structural and functional changes in GDM, but the impact of these alterations on placental trophoblast function remains unclear. During their differentiation, villous cytotrophoblast display several characteristics of senescent cells; however, the role of senescence pathways in placental function remains unexplored in normoglycemic as well as GDM pregnancies. Here, we investigate placental senescence pathways utilizing term villous tissue and primary trophoblasts to assess senescence pathways and determine fetal sex-based differences in normoglycemic and GDM pregnancies. Our data suggest that both p21- and p16-mediated senescence pathways are activated during trophoblast differentiation and are dysregulated in the GDM placenta in a sexually dimorphic manner. We also provide evidence for increased activation of p53-Lamin A/C and p16-RB pathways in trophoblasts from GDM placentas. Reduced expression of p21 and its downstream effects on GCM1 expression and βhCG secretion outline how altered physiological senescence can affect trophoblast differentiation and function. This is an important study highlighting the disruption of placental senescence pathways in pregnancies complicated by GDM.