GDM Effect on Maternal and Neonatal Endothelial Progenitors and Vascular Function

描述（由申请人提供）：妊娠期糖尿病（GDM）很常见，约占所有妊娠的4%。很大一部分患有GDM的女性在10年内发展为II型糖尿病。此外，既往有GDM病史的未怀孕妇女也表现出血管功能障碍。重要的是，与糖尿病相关的血管疾病对这种慢性疾病的发病率和死亡率有显著影响。然而，糖尿病导致血管疾病的机制尚不清楚。此外，越来越多的证据表明，患有糖尿病的宫内环境增加了后代患慢性成人疾病的风险，包括II型糖尿病、代谢综合征和高血压。总的来说，这些观察结果构成了我们整体假设的基础。我们假设胎儿暴露于糖尿病宫内环境会加速血管功能障碍的发生，并增加成人血管疾病发展的风险。血管健康的一个关键组成部分是内皮祖细胞（EPCs）对受损内皮的有效修复和形成新血管的能力。然而，先前评估高血糖对EPC功能影响的研究的一个主要限制是未能使用定义其他干细胞/祖细胞群的原则来识别EPCs，包括高度增殖性质、自我更新能力和体内新生血管形成。我们计划研究高血糖对两种细胞群的影响，这两种细胞群先前被证明有助于血管生成：CFU-ECs（血管生成造血细胞）和ecfc（内皮祖细胞群）。在具体目标1中，我们将研究高血糖对正常足月分娩脐带血CFU-ECs和ecfc的影响。在特异性目标2中，我们将评估GDM母亲的婴儿是否表现出CFU-EC和ECFC功能减弱以及血管反应性改变。最后，我们将研究母体血糖控制是否与母体和婴儿CFU-EC和ECFC功能相关。了解母体糖尿病引起后代血管疾病的机制将可能阐明潜在的预防策略，并为这些个体的治疗提供进展。此外，对新生儿和婴儿的研究提供了识别成人疾病风险的早期预测因素或生物标志物的潜力，从而可以实施早期干预，以破坏或逆转这一过程，并影响不断升级的卫生保健问题。概要：患有妊娠期糖尿病的母亲所生的婴儿患成人疾病的风险增加，包括血管疾病。我们将检测患有妊娠糖尿病的母亲所生的婴儿是否有修复和生成新血管的细胞功能异常。

DESCRIPTION (provided by applicant): Gestational diabetes (GDM) is common, occurring in approximately 4% of all pregnancies. A large proportion of women with GDM develop Type II DM within 10 years. In addition, nonpregnant women with a prior history of GDM exhibit vascular dysfunction. Importantly, vascular diseases associated with DM contribute significantly to the morbidities and mortality of this chronic disease. However, the mechanism by which DM leads to vascular disease is unknown. Furthermore, emerging evidence suggest that the diabetic intrauterine environment increases the risk for offspring to develop chronic adult diseases including Type II DM, the metabolic syndrome, and hypertension. Collectively, these observations form the basis for our overall hypothesis. We hypothesize that fetal exposure to a diabetic intrauterine environment accelerates the onset of vascular dysfunction and increases the risk for the development of adult vascular disease. A critical component of vascular health is efficient repair of damaged endothelium and ability to form new blood vessels by endothelial progenitor cells (EPCs). However, a major limitation to previous studies assessing the effect of hyperglycemia on EPC function was the failure to identify EPCs using principals that define other stem/progenitor cell populations including highly proliferative nature, self-renewal capacity, and de novo vessel formation in vivo. We plan to examine the effect of hyperglycemia on two cell populations previously shown to contribute to angiogenesis: CFU-ECs, angiogenic hematopoietic cells, and ECFCs, an endothelial progenitor population. In Specific Aim 1, we will examine the effect of hyperglycemia on cord blood CFU-ECs and ECFCs obtained from normal full-term deliveries. In Specific Aim 2, we will evaluate whether infants of mothers with GDM exhibit diminished CFU-EC and ECFC function as well as altered vascular reactivity. Finally, we will examine whether maternal glycemic control correlates with maternal and infant CFU-EC and ECFC function. Understanding the mechanism(s) by which maternal DM elicits vascular disease in her offspring will likely elucidate potential prevention strategies as well as provide advances in the treatment of these individuals. Furthermore, studies in neonates and infants offer the potential to identify early predictors or biomarkers of adult disease risk such that early intervention may be implemented to disrupt or reverse this process and impact an escalating health care problem. Lay summary: Infants born to mothers with gestational diabetes are at increased risk to develop adult diseases, including diseases of the blood vessels. We will test whether infants born to mothers with gestational diabetes have abnormal function of cells that repair and make new blood vessels.