Abstract Background Gestational diabetes (GD) is a common pregnancy complication with well-documented perinatal consequences for the offspring. Beyond these immediate effects, children born to women with GD face a higher risk of developing atherosclerotic cardiovascular disease (ASCVD) later in life, though the underlying mechanisms remain unclear. We hypothesize that an altered circulating environment in GD-offspring may impair vascular function, elevating their ASCVD risk. Purpose To elucidate whether the circulating environment of adolescents born to GD mothers affects vascular function. Methods Plasma samples were collected from adolescents (aged 12-15 years) born to normoglycemic (n=8) or GD (n=12) mothers. Freshly isolated aortas from C57BL/6 mice were incubated with 10% plasma for 24 hours. After treatment, endothelium-dependent and -independent responses (EDR and EIR, respectively) to acetylcholine and sodium nitroprusside were assessed ex vivo using wire myography. In another set of experiments, aortas were also incubated with the anti-oxidant agents Tempol and NAC or vehicle. For in vitro studies, human aortic endothelial cells (HAECs) incubated with 10% plasma for 24 hours were used for different analyses: gene expression of different markers of oxidative stress and inflammation was evaluated using RT-PCR, production of reactive oxygen species (ROS; O2- and ONOO-) were measured by electron spin resonance (ESR) spectroscopy, and endothelial activation through a monocyte adhesion assay. Finally, ROS levels were measured directly in the plasma samples. Results Mouse aortas exposed to GD plasma exhibited reduced EDR compared to those incubated with control plasma, whereas EIR remained unaffected, indicating endothelial dysfunction. Notably, the GD plasma-induced EDR impairment was rescued by the antioxidant compounds Tempol and NAC, confirming oxidative stress as a key mediator. Consistently, HAECs exposed to GD plasma showed elevated mRNA expression of both anti- (CAT, GPX1, PRDX1, SOD1, SOD2) and pro- (NOX4, COX1, COX2) oxidant genes, along with increased ROS production. Additionally, pro-inflammatory genes (NF-κB, ICAM1, IL18) were upregulated and monocyte adhesion was enhanced in these cells, suggesting an inflammatory endothelial phenotype. Interestingly, no significant differences were detected in ROS levels in the plasma samples, indicating that the pathological responses of GD plasma can not be attributed to increased circulating ROS. Future research will be focused on the identification of the circulating factors driving these effects. Conclusion Our results suggest that adolescents exposed to GD in utero have an altered circulating environment that may compromise endothelial function through oxidative stress and inflammation, potentially contributing to an elevated ASCVD risk. These findings may inform preventive and therapeutic strategies to tackle the onset of cardiovascular complications in this vulnerable population.
Ceinos et al. (Sat,) studied this question.