New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects.
New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects.
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DOI：
10.1016/j.ajog.2015.09.082
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发表时间：
2016-02
影响因子：
9.8
通讯作者：
Yang P
中科院分区：
文献类型：
--
作者：
Dong D;Reece EA;Lin X;Wu Y;AriasVillela N;Yang P
产妇糖尿病是结构性出生缺陷的重要危险因素，包括先天性心脏缺陷和神经管缺陷（NTDs）。随着育龄妇女中2型糖尿病和肥胖症患病率的上升，糖尿病引起的出生缺陷已成为一个日益重要的公共卫生问题。母体体内糖尿病和体外高糖通过破坏细胞形态和改变细胞器动力学诱导卵黄囊损伤。卵黄囊血管系统是胚胎发生过程中最先发育的系统，因此对高血糖最为敏感。卵黄囊损伤的后果包括由于血管病变导致的营养物质运输障碍。尽管卵黄囊血管病变与结构性出生缺陷之间的功能关系尚未确定，但最近的一项研究表明，卵黄囊血管质量与胚胎畸形率呈负相关。动物模型研究揭示了糖尿病卵黄囊血管病变的关键分子中间体，包括缺氧诱导因子-1α (HIF-1α)、凋亡信号调节激酶1 （ASK1）及其抑制剂硫氧还蛋白-1 （Trx）、c- jun - n末端激酶（JNK）、一氧化氮（NO）和一氧化氮合酶（NOS）。卵黄囊血管病变也与花生四烯酸和肌醇异常有关。膳食补充脂肪酸，恢复卵黄囊中的脂质水平，减少糖尿病引起的畸形。尽管人类卵黄在胚胎发生中的作用不如啮齿动物广泛，但母体糖尿病对人类胚胎血管发生有负面影响。机制研究已经确定了未来干预卵黄囊血管病变、出生缺陷和其他与糖尿病妊娠相关的并发症的潜在治疗靶点。
Maternal diabetes is a significant risk factor for structural birth defects, including congenital heart defects and neural tube defects (NTDs). With the rising prevalence of type 2 diabetes and obesity in women of childbearing age, diabetes-induced birth defects have become an increasingly significant public health problem. Maternal diabetes in vivo and high glucose in vitro induce yolk sac injuries by damaging the morphology of cells and altering the dynamics of organelles. The yolk sac vascular system is the first system to develop during embryogenesis, therefore, it is the most sensitive to hyperglycemia. The consequences of yolk sac injuries include impairment of nutrient transportation due to vasculopathy. Although the functional relationship between yolk sac vasculopathy and structural birth defects has not yet been established, a recent study reveals that the quality of yolk sac vasculature is inversely related to embryonic malformation rates. Studies in animal models have uncovered key molecular intermediates of diabetic yolk sac vasculopathy, including hypoxia-inducible factor-1α (HIF-1α), apoptosis signal-regulating kinase 1 (ASK1) and its inhibitor thioredoxin-1 (Trx), c-Jun-N-terminal kinases (JNK), nitric oxide (NO) and nitric oxide synthase (NOS). Yolk sac vasculopathy is also associated with abnormalities in arachidonic acid and myo-inositol. Dietary supplementation with fatty acids that restore lipid levels in the yolk sac lead to reduction in diabetes-induced malformations. Although the role of the human yolk in embryogenesis is less extensive than in rodents, nevertheless, human embryonic vasculogenesis is negatively affected by maternal diabetes. Mechanistic studies have identified potential therapeutic targets for future intervention against yolk sac vasculopathy, birth defects, and other complications associated with diabetic pregnancies.