Aging Endothelial Precursor Cell Proangiogenic Function

衰老内皮前体细胞促血管生成功能

• 批准号: 7051375
• 负责人: Jay M. Edelberg
• 金额: $ 33.1万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7051375
• 关键词: Adenoviridae; aging; angiogenesis; animal old age; biotechnology; bone marrow transplantation; cardiovascular disorder prevention; gene expression; growth factor receptors; immature animal; laboratory mouse; laboratory rat; mature animal; myocardial infarction; nonhuman therapy evaluation; platelet derived growth factor; stem cell transplantation; stem cells; tissue /cell culture; transfection

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.

衰老心脏中的血管生成潜力抑郁。初步研究表明，衰老内皮细胞的变化导致心肌细胞诱导的血小板衍生的生长因子（PDGF B）介导的途径失调，这是衰老心脏血管生成活性下降的基础。 最近的研究还表明，骨髓是内皮前体细胞（EPC）的来源，可能有助于调节血管生成功能。具体而言，显示出与心肌细胞共培养时，源自年轻成年小鼠的骨髓（3个月大）的EPC被诱导表达PDGF B，而源自衰老小鼠（18个月大）的骨髓的细胞不是。 体内研究表明，通过递送PDGF AB或将幼年骨髓细胞移植到完整，未辐照的未辐射的衰老小鼠中，通过递送PDGF B-依赖性途径来恢复衰老心脏血管生成功能。 此外，这种促血管生成途径可保护衰老的心脏免受心肌梗塞的侵害。 综上所述，这些初步数据强烈支持以下假设：在衰老的骨髓中衍生出PDGF B诱导的EPC中的途径将恢复衰老的心脏血管生成功能。该项目的远程目标是通过分子恢复源自衰老的骨髓的EPC的活性来特异性增强衰老心脏的血管生成活性。 PDGF B诱导途径途径的关键要素将在较旧的骨髓衍生的EPC中定义并恢复，以促进衰老心脏促肌血管生成途径的长期重构。 此外，介导PDGF B诱导的血管生成作用的临界下游基因将被定义为建立分子方案的一种手段，以限制衰老骨髓衍生的EPC的促血管生成功能的恢复到心脏脉管系统。 这些研究确定的元素和基因的生理意义将取决于它们促进心脏血管生成功能并保护衰老心脏免受心肌梗塞的能力。 总体而言，该研究计划将建立开发新方法的基础，以利用源自衰老骨髓的EPC的潜力，以治疗和预防老年人的心血管疾病。

项目成果

Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection.

生长因子介导的缺血诱导的心脏保护衰老功能障碍的逆转。

• DOI: 10.1152/ajpheart.00470.2005
• 发表时间: 2006
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Zheng,Jingang;Chin,Andrew;Duignan,Inga;Won,Kyung-Heon;Hong,MunK;Edelberg,JayM
• 通讯作者: Edelberg,JayM

Platelet-derived growth factor improves cardiac function in a rodent myocardial infarction model.

血小板衍生生长因子可改善啮齿动物心肌梗死模型中的心脏功能。

• DOI: 10.1097/00019501-200402000-00009
• 发表时间: 2004
• 期刊: Coronary artery disease
• 影响因子: 1.8
• 作者: Zheng,Jingang;Shin,JinH;Xaymardan,Munira;Chin,Andrew;Duignan,Inga;Hong,MunK;Edelberg,JayM
• 通讯作者: Edelberg,JayM