Endothelial Progenitor and Vascular Dysfunction in Infants of Diabetic Mothers

描述(由申请人提供)：重要的证据表明，子宫内环境不利会增加后代患血管疾病的风险。虽然最初的报告集中在生长受限的婴儿，但数据表明，母亲糖尿病(DM)使子女容易患血管疾病。总而言之，这些数据表明胎儿的血管系统对损伤非常敏感。血管健康的一个重要组成部分是完整的内皮功能。内皮的动态平衡调节需要内皮细胞和血液循环中的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(EPC)协调血管修复和血管形成。此外，在成人中的大量研究表明，外周血内皮祖细胞数量减少与血管疾病风险增加的功能之间存在相关性。然而，还没有研究检验儿童是否存在类似的相关性。这些数据共同构成了我们总体假设的基础。我们假设，母体型2型糖尿病(T2 DM)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，并增加子代发生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仪进行鉴定。已经报道了两个具有不同功能特性的EPC亚群。然而，很少有研究评估来自儿科受试者的这些内皮祖细胞的功能，尽管有数据表明这两种类型的内皮祖细胞在血管修复中都是有效的。本申请中概述的研究将直接询问这两个EPC亚群的功能障碍是否与T2 DM妊娠后代的内皮功能障碍有关，并检查过早衰老对EPC功能能力的贡献。阐明导致T2 DM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记物的可能性，以便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型糖尿病母亲的后代内皮功能障碍有关。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。

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.