EFFECTS OF AGING ON BLOOD-DERIVED ENDOTHELIAL CELLS

本提案是对项目目标5 -干细胞、组织修复和衰老中的细胞替代的回应。我们的目标是确定血液来源的内皮细胞前体（成血管细胞）的损伤是否有助于与衰老相关的心血管疾病。在这项研究中，我们将确定成人血液来源的成血管细胞的分化，增殖和纳入血管系统的能力是否会因衰老而改变。血液来源的成血管细胞似乎在血管内皮的常规维持中起作用，并且在一些血管生成模型中，新生血管中多达10%的内皮细胞是血液来源的。成血管细胞与造血干细胞相关或相同。造血干细胞的增殖能力和细胞数量可能随着年龄的增长而下降，这表明成血管细胞可能同样受到衰老的影响。此外，成血管细胞功能在糖尿病中改变，并且许多严重的心血管并发症与糖尿病相关。 基于这些和相关的发现，我们假设衰老损害成血管细胞的功能。这种损伤可能导致与衰老相关的血管问题。为了验证我们的假设，我们将1）比较来自年轻人和老年人的成血管细胞在体外增殖和分化的能力，2）确定衰老是否影响血液来源的细胞并入新血管系统的程度。 后一实验将通过将人成血管细胞注射到由于后肢缺血而经历血管生成的小鼠中来完成。 在这项研究中，我们将回答三个问题。首先，来自脐带、年轻人和老年人的血液是否具有相同的血管生成潜能？第二，成血管细胞融入老年小鼠新血管系统的能力是否受损？第三，来自老年人的成血管细胞是否具有降低的并入新血管系统或改善缺血小鼠血流的能力？在回答这些问题时，将确定衰老是否会改变成血管细胞功能的几个方面，包括恢复缺血组织血流的能力。 降低的成血管细胞功能表明成血管细胞在衰老相关的心血管并发症中起作用，并且成血管细胞可能是设计用于预防或纠正的治疗的重要靶点。

This proposal is in response to program objective 5 - Stems Cells, Tissue Repair, and Cell Replacement in Aging. Our goal is to determine if impairment of blood-derived endothelial cell precursors (angioblasts) contributes to cardiovascular disease associated with aging. In this study we will determine if the ability of adult blood-derived angioblasts to differentiate, proliferate, and incorporate into the vasculature is altered by aging. Blood-derived angioblasts appear to function in the routine maintenance of vascular endothelium, and in some models of angiogenesis, as many as 10% of endothelial cells in the neovasculature are blood-derived. Angioblasts are related or identical to hematopoietic stem cells. Hematopoietic stem cell proliferative ability and possibly cell number decrease with age, suggesting that angioblasts might be similarly affected by aging. Additionally, angioblast function is altered in diabetes, and numerous and severe cardiovascular complications are associated with diabetes. Based on these and related findings, we hypothesize that aging impairs angioblast function. This impairment may contribute to vascular problems associated with aging. To test our hypothesis we will 1) compare the ability of angioblasts derived from young and older adults to proliferate and differentiate in Vitro, and 2) determine if aging influences the extent to which blood-derived cells incorporate into the neovasculature. The latter experiments will be accomplished by injecting human angioblasts into mice undergoing angiogenesis due to hindlimb ischemia. In this study we will answer three questions. First, does blood derived from umbilical cords, young adults, and older adults carry the same angioblastic potential? Secondly, is the ability of angioblasts to incorporate into the neovasculature of aged mice impaired? Thirdly, do angioblasts derived from older adults have a reduced capacity to incorporate into the neovasculature or to improve blood flow in ischemic mice? In answering these questions will ascertain whether aging alters several aspects of angioblast function, including the ability to restore blood flow to ischemic tissue. Reduced angioblast function would suggest that angioblasts play a role in aging associated cardiovascular complications, and that angioblasts may be an important target for therapies designed to prevent or correct.