Novel insights for the role of nitric oxide in placental vascular function during and beyond pregnancy

Abstract More than 30 years have passed since endothelial nitric oxide synthesis was described using the umbilical artery and vein endothelium. That seminal report set the cornerstone for unveiling the molecular aspects of endothelial function. In parallel, the understanding of placental physiology has gained growing interest, due to its crucial role in intrauterine development, with considerable long‐term health consequences. This review discusses the evidence for nitric oxide (NO) as a critical player of placental development and function, with a special focus on endothelial nitric oxide synthase (eNOS) vascular effects. Also, the regulation of eNOS‐dependent vascular responses in normal pregnancy and pregnancy‐related diseases and their impact on prenatal and postnatal vascular health are discussed. Recent and compelling evidence has reinforced that eNOS regulation results from a complex network of processes, with novel data concerning mechanisms such as mechano‐sensing, epigenetic, posttranslational modifications, and the expression of NO‐ and l ‐arginine‐related pathways. In this regard, most of these mechanisms are expressed in an arterial‐venous‐specific manner and reflect traits of the fetal systemic circulation. Several studies using umbilical endothelial cells are not aimed to understand placental function but general endothelial function, reinforcing the influence of the placenta on general knowledge in physiology.