Aging Endothelial Precursor Cell Proangiogenic Function

老化心脏的血管生成潜能受到抑制。初步研究表明，衰老内皮细胞的改变导致心肌细胞诱导的血小板衍生生长因子（PDGF B）介导途径的失调，这是衰老心脏血管生成活性下降的基础。最近的研究也表明，骨髓是内皮前体细胞（EPCs）的来源，可能有助于血管生成功能的调节。具体来说，研究表明，当与心肌细胞共培养时，来自年轻成年小鼠（3个月大）骨髓的EPCs被诱导表达PDGF B，而来自衰老小鼠（18个月大）骨髓的细胞则没有。体内研究表明，通过输送PDGF AB或将年轻骨髓细胞移植到完整、未辐照的衰老小鼠体内，重建PDGF B依赖通路可以恢复衰老的心脏血管生成功能。此外，这种促血管生成途径保护老化的心脏免受心肌梗死。综上所述，这些初步数据有力地支持了一种假设，即在来自衰老骨髓的EPCs中重建PDGF b诱导的通路将恢复衰老的心脏血管生成功能。该项目的长期目标是通过分子恢复来自衰老骨髓的内皮祖细胞的活性来特异性地增强老化心脏的血管生成活性。PDGF B诱导上游通路的关键元件将在老年骨髓来源的EPCs中被定义和恢复，以促进衰老心脏促血管生成通路的长期重建。此外，介导PDGF B诱导血管生成作用的关键下游基因集将被定义为建立分子方案的手段，以限制老化的骨髓来源的EPCs对心脏血管的促血管生成功能的恢复。这些研究发现的元素和基因的生理意义将通过它们促进心脏血管生成功能和保护老化心脏免受心肌梗死的能力来确定。总的来说，这项研究计划将为开发新的方法奠定基础，利用来自衰老骨髓的内皮祖细胞的潜力，治疗和预防老年人心血管疾病。

Angiogenic potential in the aging heart is depressed. Preliminary studies have revealed that alterations in aging endothelial cells result in the dysregulation of a cardiac myocyte-induced platelet-derived growth factor (PDGF B)-mediated pathway that underlies the decline in senescent cardiac angiogenic activity. Recent studies have also demonstrated that the bone marrow is a source of endothelial precursor cells (EPCs) that may contribute to the regulation of angiogenic function. Specifically, it was shown that when co-cultured with cardiac myocytes, EPCs derived from the bone marrow of young adult mice (3 months old) are induced to express PDGF B, whereas cells derived from the bone marrow of aging mice (18 months old) are not. In vivo studies revealed that reconstitution of the PDGF B- dependent pathways by delivery of PDGF AB or transplantation of young bone marrow cells into intact, unirradiated aging mice restores senescent cardiac angiogenic function. Moreover, this proangiogenic pathway protects the aging heart from myocardial infarction. Taken together, these preliminary data strongly support the hypothesis that reconstitution of the PDGF B-induced pathways in EPCs derived from the aging bone marrow will restore senescent cardiac angiogenic function. The long-range goals of this project are to specifically enhance angiogenic activity in the aging heart by the molecular restoration of the activity of EPCs derived from the aging bone marrow. The critical elements of the pathways upstream of PDGF B induction will be defined and restored in older bone marrow- derived EPCs to promote the long-term reconstitution of the senescent cardiac proangiogenic pathways. In addition, the critical set of downstream genes mediating the angiogenic actions of PDGF B induction will be defined as a means of establishing molecular regimens to restrict the restoration of proangiogenic function of aging bone marrow-derived EPCs to the cardiac vasculature. The physiological significance of the elements and genes identified by these studies will be defined by their ability to promote cardiac angiogenic function and protect the aging heart from myocardial infarction. Overall this research plan will establish a foundation for development of novel approaches to exploit the potential of EPCs derived from the aging bone marrow for the treatment and possible prevention of cardiovascular diseases in older persons.