Restoration of Senescent Cardiac Angiogenic Potential

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-表皮生长因子（EGF）-血小板衍生生长因子（PDGF）途径的失调，这是衰老心脏血管生成活性下降的基础。年轻小鼠心脏的内皮细胞表达EGF受体（EGFR），其介导心肌细胞诱导的PDGF B的内皮表达。这导致PDGF AB的产生，其已被证明可调节心脏中内皮细胞的活性。当在心肌细胞存在下培养时，衰老心脏的内皮细胞缺乏EGFR并且不表达PDGF B。腺病毒介导的EGFR表达特异性地恢复了衰老内皮细胞中的PDGF B诱导。体内研究表明，通过递送EGFR或PDGF AB重建PDGF B依赖性途径恢复衰老的心脏血管生成功能，此外，这种促血管生成途径具有心脏保护作用，降低冠状动脉结扎后心肌梗死的程度。总之，这些数据有力地支持了这样的假设，即在衰老心脏的内皮细胞中重建PDGF B介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心脏内皮细胞功能的分子恢复来特异性地增强衰老心脏中的血管生成活性。介导PDGF B诱导的EGFR结构域将在老年心脏内皮细胞中被定义和恢复，以促进衰老心脏促血管生成途径的长期特异性重建。此外，增强PDGF AB的促血管生成作用的内皮基因组将被定义为增加该方法在恢复衰老心脏血管生成活性中的效力的手段。这些策略的功能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证实。总的来说，这些研究将有助于开发治疗和可能预防老年人心血管疾病的新方法。

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.