Hyperglycaemia observed during pre-gestational or gestational diabetes impacts placental and foetal development. O-GlcNAcylation (O-GlcNAc), a post-translational modification increased in diabetes, disrupts signalling pathways involved in angiogenesis and hypoxic stress response, aggravating poor vascularization. In rat neonatal and adult mouse cardiomyocytes, this dysregulation contributes to cardiac hypertrophy by amplifying metabolic stress, inflammation and myocardial remodelling. We postulate that an increase in O-GlcNAc levels associated with maternal hyperglycaemia could be a major determinant in the alteration of placental vascularization and in the development of paediatric cardiac hypertrophy.

This project aims to explore how hyper-O-GlcNAcylation (linked to gestational hyperglycaemia) could affect heart development and induce cardiac pathologies observed in infants delivered from diabetic mothers, and to understand how O-GlcNAc balance modulates placental vasculogenesis and angiogenesis.

NButGT (10mg/kg) was administered throughout gestation to increase O-GlcNAc level in embryo. Heart and placenta were harvested at 2 different time points: 15.5 and 20.5 embryonic days to evaluate both O-GlcNAc pathway and vasculogenesis and angiogenesis placental and heart (ZO1, VEGF, NO pathway, ROS markers, permeability markers).

Treatment with NButGT efficiently increased O-GlcNAc level in heart (E20.5: P<0.0001; E15.5: P=0.0427) and placenta (E20.5: P=0.07). This increase had a strong impact on cardiac (with a loss of weight at E20.5: P<0.02) and placental development as evidenced by a decrease in placental weight (E20.5: P<0.0001). Also, high level of O-GlcNAc levels during development was associated with a modification of the expression of VEGFR2 (decrease) and ZO1 (increase) both in heart (data not shown) and placenta (E15.5: P<0.001; and E15.5: P=0.095; E20.5: P=0.05, respectively).

Hyper-O-GlcNAcylation altered foetal development during gestation. Understanding the consequences of hyper-O-GlcNAcylation related to hyperglycaemia during foetal development could significantly advance research and patient treatment, potentially identifying new drug targets.