Protein O-GlcNAcylation as a nutrient sensor signaling placental dysfunction in hypertensive pregnancy

Abstract

IntroductionDuring pregnancy, arterial hypertension may impair placental function, which is critical for a healthy baby's growth. Important proteins during placentation are known to be targets for O-linked β-N-acetylglucosamine modification (O-GlcNAcylation), and abnormal protein O-GlcNAcylation has been linked to pathological conditions such as hypertension. However, it is unclear how protein O-GlcNAcylation affects placental function and fetal growth throughout pregnancy during hypertension.MethodsTo investigate this question, female Wistar and spontaneously hypertensive rats (SHR) were mated with male Wistar rats, and after pregnancy confirmation by vaginal smear, rats were divided into groups of 14, 17, and 20 days of pregnancy (DOPs). On the 14th, 17th, and 20th DOP, rats were euthanized, fetal parameters were measured, and placentas were collected for western blot, immunohistochemical, and morphological analyses.ResultsSHR presented a higher blood pressure than the Wistar rats (p=0.001). Across all DOPs, SHR showed reduced fetal weight and an increase in small-for-gestational-age fetuses. While near-term placentas were heavier in SHR (p=0.006), placental efficiency decreased at 17 (p=0.01) and 20 DOPs (p<0.0001) in this group. Morphological analysis revealed reduced junctional zone area and labyrinth vasculature changes on SHR placentas in all DOPs. O-GlcNAc protein expression was lower in placentas from SHR compared with Wistar at 14, 17, and 20 DOPs. Decreased expression of O-GlcNAc transferase (p=0.01) and O-GlcNAcase (p=0.002) enzymes was found at 14 DOPs in SHR. Immunohistochemistry showed reduced placental O-GlcNAc content in both the junctional zone and labyrinth of the placentas from SHR. Periodic acid-Schiff analysis showed decreased glycogen cell content in the placentas from SHR at 14, 17, and 20 DOPs. Moreover, glucose transporter 1 expression was decreased in placentas from SHR in all DOPs.ConclusionsThese findings suggest that decreased protein O-GlcNAcylation caused by insufficient placental nutritional apport contributes to placental dysfunction during hypertensive pregnancy, impairing fetal growth.

Regulators involved in trophoblast syncytialization in the placenta of intrauterine growth restriction

“…Fetal growth is a continuous process in which cells, tissues, and organs differentiate and undergo maturation. During this process, the transport of primary nutrients, such as glucose, amino acids, and lipids, is essential for the development of a healthy baby ( 11 ). The placenta not only maintains the pregnant state and protects the embryo from infection, but also promotes the exchange of nutrients, gases, and waste products so that the embryo can safely survive and grow in a healthy intrauterine environment ( 12 ).…”

“…This condition may lead to fetal growth restriction and fetal hypoxia, and in severe cases, irreversible ischemic organ damage and intrauterine fetal death may occur ( 13 ). Recent study findings suggested that insufficient placental nutrition transport during hypertensive pregnancy impairs fetal growth by decreasing placental protein O-GlcNAcylation ( 11 ). The proper functioning of the placenta depends on the integrity of its structure, which involves trophoblasts, immune cells and other placental cells proliferating, differentiating, and undergoing apoptosis at proper rates and in a balanced state.…”