Diabetes Research Envisioned and Accomplished in Manitoba (DREAM), Research Theme of the Children's Hospital Research Institute of Manitoba, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada.
Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada.
Int J Mol Sci. 2022 Apr 29;23(9):4970. doi: 10.3390/ijms23094970.
Gestational diabetes mellitus (GDM) increases risk of adverse pregnancy outcomes and maternal cardiovascular complications. It is widely believed that maternal endothelial dysfunction is a critical determinant of these risks, however, connections to maternal cardiac dysfunction and mechanisms of pathogenesis are unclear. Circulating extracellular vesicles (EVs) are emerging biomarkers that may provide insights into the pathogenesis of GDM. We examined the impact of GDM on maternal cardiac and vascular health in a rat model of diet-induced obesity-associated GDM. We observed a >3-fold increase in circulating levels of endothelial EVs (p < 0.01) and von Willebrand factor (p < 0.001) in GDM rats. A significant increase in mitochondrial DNA (mtDNA) within circulating extracellular vesicles was also observed suggesting possible mitochondrial dysfunction in the vasculature. This was supported by nicotinamide adenine dinucleotide deficiency in aortas of GDM mice. GDM was also associated with cardiac remodeling (increased LV mass) and a marked impairment in maternal diastolic function (increased isovolumetric relaxation time [IVRT], p < 0.01). Finally, we observed a strong positive correlation between endothelial EV levels and IVRT (r = 0.57, p < 0.05). In summary, we observed maternal vascular and cardiac dysfunction in rodent GDM accompanied by increased circulating endothelial EVs and EV-associated mitochondrial DNA. Our study highlights a novel method for assessment of vascular injury in GDM and highlights vascular mitochondrial injury as a possible therapeutic target.
妊娠期糖尿病（GDM）会增加不良妊娠结局和母体心血管并发症的风险。人们普遍认为，母体血管内皮功能障碍是这些风险的关键决定因素，然而，与母体心脏功能障碍的联系和发病机制尚不清楚。循环细胞外囊泡（EVs）是新兴的生物标志物，可能为 GDM 的发病机制提供深入了解。我们在饮食诱导肥胖相关 GDM 的大鼠模型中研究了 GDM 对母体心脏和血管健康的影响。我们观察到 GDM 大鼠循环内皮 EVs（p < 0.01）和血管性血友病因子（von Willebrand factor，vWF；p < 0.001）水平增加了 3 倍以上。还观察到循环细胞外囊泡内线粒体 DNA（mtDNA）的显著增加，这表明血管中可能存在线粒体功能障碍。这得到了 GDM 小鼠主动脉中烟酰胺腺嘌呤二核苷酸缺乏的支持。GDM 还与心脏重构（左心室质量增加）和母体舒张功能明显受损（等容舒张时间增加[IVRT]，p < 0.01）有关。最后，我们观察到内皮 EV 水平与 IVRT 之间存在强烈的正相关（r = 0.57，p < 0.05）。总之，我们在 GDM 啮齿动物中观察到母体血管和心脏功能障碍，同时伴有循环内皮 EVs 和 EV 相关 mtDNA 增加。我们的研究强调了一种评估 GDM 血管损伤的新方法，并强调了血管线粒体损伤作为一种潜在的治疗靶点。
