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-epidermal growth factor (EGF)- platelet-derived growth factor (PDGF) pathway that underlies the decline in senescent cardiac angiogenic activity. Endothelial cells of the young murine heart express the EGF receptor (EGFR) which mediates the cardiac myocyte-induced endothelial expression of PDGF B. This leads to the generation of PDGF AB that has been demonstrated to regulate the activity of endothelial cells in the heart. Endothelial cells of the aging heart lack EGFR and do not express PDGF B when cultured in the presence of cardiac myocytes Adenoviral-mediated expression of EGFR specifically restores PDGF B induction in the older endothelial cells. In vivo studies revealed that reconstitution of the PDGF B-dependent pathways by delivery of EGFR or PDGF AB restores senescent cardiac angiogenic function moreover, this pro-angiogenic pathway us cardioprotective, reducing the extent of myocardial infarction following coronary ligation. Taken together, these data strongly support the hypothesis that reconstitution of the PDGF B-mediated pathways in the endothelial cells of the aging heart will restore senescent cardiac angiogenic function. The long-range goal of this project is to specifically enhance angiogenic activity in the aging heart by the molecular restoration of cardiac endothelial cell function. The EGFR domains mediating PDGF B induction will be defined and restored in older cardiac endothelial cells to promote the long-term specific reconstitution of the senescent cardiac pro-angiogenic pathways. In addition, the set of endothelial genes augmenting the pro-angiogenic actions of PDGF AB will be defined as a means of increasing the potency of this approach in the restoration of senescent cardiac angiogenic activity. The functional significance of these strategies will be confirmed by their ability to promote cardiac angiogenic function and protect the aging heart from myocardial infarction. Overall these studies will facilitate the development of novel approaches for the treatment and possible prevention of cardiovascular diseases in older persons.
