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.

老年心脏血管生成潜能降低。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）介导的途径失调，该途径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（EPCs）的来源，可能有助于调节血管生成功能。具体地说，当与心肌细胞共培养时，来自年轻成年小鼠（3月龄）的骨髓的EPC被诱导表达PDGF B，而来自老龄小鼠（18月龄）的骨髓的细胞则不表达。 体内研究显示，通过将PDGF AB递送或将年轻骨髓细胞移植到完整的、未照射的衰老小鼠中来重建PDGF B依赖性途径可恢复衰老的心脏血管生成功能。 此外，这种促血管生成途径可以保护衰老的心脏免受心肌梗死的影响。 综上所述，这些初步的数据有力地支持了这样的假设，即在来自老化骨髓的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老化骨髓的EPCs的活性来特异性增强老化心脏中的血管生成活性。 PDGF B诱导上游途径的关键要素将在较老的骨髓来源的EPCs中被定义和恢复，以促进衰老的心脏促血管生成途径的长期重建。 此外，介导PDGF B诱导的血管生成作用的下游基因的关键集合将被定义为建立分子方案以限制老化骨髓来源的EPCs的促血管生成功能恢复至心脏脉管系统的手段。 通过这些研究鉴定的元件和基因的生理学意义将通过它们促进心脏血管生成功能和保护衰老心脏免于心肌梗死的能力来定义。 总的来说，这项研究计划将为开发新方法奠定基础，以利用来自衰老骨髓的EPCs治疗和预防老年人心血管疾病的潜力。

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