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.
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