O papel da O-glicosilação com N-acetilglucosamina na gestação

• Autor(a) principal: Dela Justina, Vanessa
• Data de Publicação: 2021
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da UFG
• dARK ID: ark:/38995/0013000004mb0
• Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/11543
• topic: O-GlcNAc; Placenta; Artéria uterina; Progesterona; Relaxamento; O-GlcNAc; Placenta; Uterine artery; Progesterone; Relaxation; CIENCIAS BIOLOGICAS::FARMACOLOGIA::FARMACOLOGIA CLINICA

O-linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification that modulates several proteins. The increase in O-Glycosylation is observed during hyperglycemia, favoring endothelial dysfunction as well as placental modifications. The hypothesis of this work was that the increase in O-Glycosylation during pregnancy, generates vascular and placental dys- function, resulting in inadequate nutritional support between the maternal -fetal interface. For this, the work was divided in two parts. PART I: To characterize how different glycemic levels affect O-GlcNAcylation of cells in different placental regions. Female Wistar rats were divided into the following groups: severe hyperglycemia (>300 mg/dL; n= 5); mild hyperglycemia (> 140 mg/dL, at least two moments in the oral glucose tolerance test; n= 7) or normoglycemia (<120 mg/dL; n= 5). Cells in the labyrinth and junctional zones are targeted by the accumu- lation of O-GlcNAc in response to severe hyperglycemia, possibly due to reduced O-GlcNAcase (OGA) expression. O-GlcNAc is not seen during mild hyperglycemia, possibly due to OGA compensatory expression/activity. In addition, morphometric changes, occurring simultane- ously with increased accumulation of O-GlcNAc in placental tissue, can contribute to placental dysfunction during hyperglycemia. PART II:) To assess whether the increase in O-GlcNAc impairs the endothelial function of the uterine artery. Pregnant (P) or non-pregnant (NP) rats were treated with glucosamine (300mg/kg) or vehicle for 21 days, i.p. Glucosamine treatment increased the expression of O-GlcNAc in UA in NP rats. A decrease in endothelium-dependent relaxation was observed in UA of treated NP rats, compared to the vehicle, which was abo- lished by incubation of the nitric oxide synthase inhibitor (eNOS). eNOS activity as well as total Akt expression are reduced after treatment with glucosamine in NP rats. In addition, UAs from NP rats treated with glucosamine showed an increase in the activation of glycogen sy n- thase kinase 3 beta (GSK3β), as well as an increase in the expression of OGT. Interestingly, during pregnancy, treatment with glucosamine decreases the expression of O-GlcNAc in UA, accompanied by an improvement in relaxation for acetylcholine, while the activities of eNOS and GSK3β and the total expressions of Akt and OGT remained unchanged. Endothelium- independent relaxation was not altered in the groups studied. Therefore, the underlying me- chanism that occurs between P and NP is, at least in part, dependent on Akt/GSK3β/OGT mo- dification. We believe that, during pregnancy, hormonal changes play a vascular protective role, preventing endothelial dysfunction induced by O-glycosylation. In the future, it will be interesting to assess whether strategies that normalize O-GlcNAcylation levels in placental proteins will result in gestational success in pathological conditions, including hyperglycemia.