Physiological and pathological evidence of O-GlcNAcylation regulation during pregnancy related process.

O-GlcNAcylation is a dynamic and reversible post-translational modification (PTM) controlled by the enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Changes in its expression lead to a breakdown in cellular homeostasis, which is linked to several pathological processes. Placentation and embryonic development are periods of high cell activity, and imbalances in cell signaling pathways can result in infertility, miscarriage, or pregnancy complications. O-GlcNAcylation is involved in cellular processes such as genome maintenance, epigenetic regulation, protein synthesis/degradation, metabolic pathways, signaling pathways, apoptosis, and stress response. Trophoblastic differentiation/invasion and placental vasculogenesis, as well as zygote viability and embryonic neuronal development, are all dependent on O-GlcNAcylation. This PTM is required for pluripotency, which is a required condition for embryonic development. Further, this pathway is a nutritional sensor and cell stress marker, which is primarily measured by the OGT enzyme and its product, protein O-GlcNAcylation. Yet, this post-translational modification is enrolled in metabolic and cardiovascular adaptations during pregnancy. Finally, evidence of how O-GlcNAc impacts pregnancy during pathological conditions such as hyperglycemia, gestational diabetes, hypertension, and stress disorders are reviewed. Considering this scenario, progress in understanding the role of O- GlcNAcylation in pregnancy is required.

O-GlcNAc impairs endothelial function in uterine arteries from virgin but not pregnant rats: The role of GSK3ß.

Increased O-Linked ß-N-acetylglucosamine (O-GlcNAc) is observed in several pathologies, and unbalanced O-GlcNAcylation levels favor endothelial dysfunction. Whether augmented O-GlcNAc impacts the uterine artery (UA) function and how it affects the UA during pregnancy remains to be elucidated. We hypothesized that glucosamine treatment increases O-GlcNAc, leading to uterine artery dysfunction and this effect is prevented by pregnancy. Pregnant (P) and non-pregnant (NP) Wistar rats were treated with glucosamine (300 mg/kg; i.p.) for 21 days. Concentration response-curves (CRC) to acetylcholine (in the presence or absence of L-NAME) and sodium nitroprusside were performed in UAs. In NP rats, glucosamine treatment increased O-GlcNAc expression in UAs accompanied by decreased endothelium-dependent relaxation, which was abolished by L-NAME. Endothelial nitric oxide synthase (eNOS) activity and total Akt expression were decreased by glucosamine-treatment in NP rats. Further, NP rats treated with glucosamine displayed increased glycogen synthase kinase 3 beta (GSK3ß) activation and O-GlcNAc-transferase (OGT) expression in the UA. P rats treated with glucosamine displayed decreased O-GlcNAc in UAs and it was accompanied by improved relaxation to acetylcholine, whereas eNOS and GSK3ß activity and total Akt and OGT expression were unchanged. Sodium nitroprusside-induced relaxation was not changed in all groups, indicating that glucosamine treatment led to endothelial dysfunction in NP rats. The underlying mechanism is, at least in part, dependent on Akt/GSK3ß/OGT modulation. We speculate that during pregnancy, hormonal alterations play a protective role in preventing O-GlcNAcylation-induced endothelial dysfunction in the UAs.

O-GlcNAc Modification During Pregnancy: Focus on Placental Environment.

Successful placentation is a key event for fetal development, which commences following embryo implantation into the uterine wall, eliciting decidualization, placentation, and remodeling of blood vessels to provide physiological exchange between embryo-fetus and mother. Several signaling pathways are recruited to modulate such important processes and specific proteins that regulate placental function are a target for the glycosylation with O-linked ß-N-acetylglucosamine (O-GlcNAc), or O-GlcNAcylation. This is a reversible post-translational modification on nuclear and cytoplasmic proteins, mainly controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAcylation has been implicated as a modulator of proteins, both in physiological and pathological conditions and, more recently, O-GlcNAc has also been shown to be an important modulator in placental tissue. In this mini-review, the interplay between O-GlcNAcylation of proteins and placental function will be addressed, discussing the possible implications of this post-translational modification through placental development and pregnancy.