NMN-SIRT1 signaling ameliorates IUGR via oxidative stress-mediated mitophagy to promote placental angiogenesis

Nicotinamide mononucleotide (NMN) is a natural anti-aging agent. However, its effects on intrauterine growth restriction (IUGR) remain insufficiently explored. This study found that daily intake of 2-5 g/d of NMN significantly enhanced placental angiogenesis and reduced the incidence of IUGR by using a pregnant sow model (Landrace × Yorkshire breed). Mechanistically, NMN upregulated SIRT1 expression in the placenta, alleviated oxidative stress in sows, placentas, and their offspring, inhibited excessive mitophagy in the placenta, and promoted angiogenesis. Furthermore, activation of the NMN-SIRT1 signaling pathway was observed to mitigate oxidative stress and mitophagy, thereby restoring the migratory capacity of porcine vascular endothelial cells (PVECs) and improving endothelial function. However, in the absence of oxidative stress, NMN-SIRT1 acts as a potent mitophagy-promoting signal, positively regulating PVEC angiogenesis. In conclusion, our study demonstrates that the activation of NMN-SIRT1 signaling is crucial for reducing adverse pregnancy outcomes by ameliorating placental dysfunction induced by perinatal oxidative stress.