Endothelial Progenitor and Vascular Dysfunction in Infants of Diabetic Mothers

描述（由申请人提供）：有重要证据表明，不利的子宫环境会增加后代患血管疾病的风险。虽然最初的报道集中在生长受限的婴儿，但数据表明，母亲糖尿病（DM）使后代易患血管疾病。综上所述，这些数据表明胎儿的血管系统极易受到损伤。血管健康的一个重要组成部分是完整的内皮功能。内皮的稳态调节需要内皮细胞和血液循环细胞之间的动态相互作用来维持内皮功能。重要的是，内皮祖细胞（EPCs）协调血管修复和血管形成。此外，许多成人研究表明，外周血EPC数量和功能减少与血管疾病风险增加之间存在相关性。然而，没有研究调查过儿童是否也存在类似的相关性。这些数据构成了我们整个假设的基础。我们假设，母亲的2型糖尿病（T2DM）宫内环境使胎儿承受显著的应激，导致EPC数量减少，EPC功能丧失，并增加后代内皮功能障碍的风险。EPC亚群可以通过培养方法和流式细胞术进行鉴定。已经报道了两个具有不同功能特性的EPC亚群。然而，很少有研究评估这两种内皮祖细胞的功能，尽管数据表明这两种内皮祖细胞在血管修复中都是有效的。本应用程序中概述的研究将直接询问两个EPC亚群的功能障碍是否与2型糖尿病妊娠后代的内皮功能障碍有关，并检查早衰对EPCs功能能力的贡献。阐明导致2型糖尿病母亲后代血管疾病风险增加的潜在机制对于寻找潜在的预防策略至关重要。此外，儿科研究提供了识别血管疾病风险的生物标志物的潜力，从而可以实施早期干预来破坏这种病理。公共卫生相关性：在本应用中，我们将直接询问内皮祖细胞功能障碍是否与2型糖尿病母亲所生后代的内皮功能障碍有关。阐明2型糖尿病母亲后代血管疾病风险增加的潜在机制对于寻找潜在的预防策略至关重要。

DESCRIPTION (provided by applicant): Significant evidence demonstrates that an adverse in utero environment increases offspring risk for vascular disease. While initial reports focused on growth restricted infants, data suggest that maternal diabetes (DM) predisposes offspring to vascular disease. Together these data suggest that the fetal vasculature is highly susceptible to injury. A critical component of vascular health is intact endothelial function. Homeostatic regulation of the endothelium requires dynamic interactions between endothelial cells and cells circulating in the blood to sustain endothelial function. Importantly, endothelial progenitor cells (EPCs) orchestrate vascular repair and vessel formation. Additionally, numerous studies in adults demonstrate a correlation between reduced peripheral blood EPC numbers and function with increased vascular disease risk. However, no studies have examined whether a similar correlation exists in children. Together these data form the basis for our overall hypothesis. We hypothesize that a maternal type 2 DM (T2DM) intrauterine environment subjects the fetus to significant stress resulting in decreased EPC numbers, loss of EPC functional capacity, and increased risk for endothelial dysfunction in offspring. EPC subpopulations can be identified by culture methods and flow cytometry. Two EPC subpopulations with distinct functional properties have been reported. However, few studies have evaluated the function of these EPCs from pediatric subjects, despite data indicating that both EPC types are operative in vascular repair. Studies outlined in this application will directly interrogate whether dysfunction of both EPC subpopulations are involved in endothelial dysfunction of offspring from T2DM pregnancies and examine the contribution of premature aging in the functional capacity of EPCs. Elucidating the underlying mechanisms responsible for the increased risk of vascular disease in offspring of T2DM mothers is paramount to finding potential preventative strategies. Further, pediatric studies offer the potential to identify biomarkers of vascular disease risk such that early interventions may be implemented to disrupt this pathology. PUBLIC HEALTH RELEVANCE: In this application, we will directly interrogate whether dysfunction of endothelial progenitor cells are involved in endothelial dysfunction of offspring from mothers with type 2 diabetes. Elucidating the underlying mechanisms responsible for the increased risk of vascular disease in offspring of type 2 diabetic mothers is paramount to finding potential preventative strategies.