Endothelial Progenitor Cells: Clinical Correlates and Prognosis in the Community

描述（由申请人提供）：内皮损伤引发一连串事件，破坏血管稳态并促进动脉粥样硬化。直到最近，人们认为，内源性修复或再生受损内皮的能力是有限的。现在已知成人外周血含有有助于血管修复和再内皮化的内皮祖细胞（EPCs）群体。早期的临床研究提出了EPCs可能作为心血管疾病（CVD）风险的新生物标志物的可能性，但这些研究受到样本量小和缺乏纵向随访的限制。我们推测CVD的易感性是由CVD危险因素介导的内皮损伤和部分由EPCs决定的内皮修复之间的平衡决定的。我们拟检验以下假设：（1）EPC数量和功能随年龄增长而下降，并与终生暴露于已知的CVD危险因素有关;（2）遗传变异影响EPC测量;（3）EPC数量和功能的减少与亚临床血管结构和功能改变有关;（4）EPC数量和功能的减少在纵向上比传统的危险因素更易发生CVD。我们建议在一个大型的前瞻性队列中评估EPC（约3500名FHS参与者在Offspring检查8和Omni检查3）。我们的具体目标是：（1）研究EPC数量和功能的临床和遗传相关性（2）探讨EPC特征与血管结构亚临床指标之间的关系（颈动脉内膜中层厚度[IMT]，颈动脉狭窄）和功能（3）分析EPC特征与CVD的关系。拟议的研究代表了FHS，马萨诸塞州总医院（MGH）心脏病科和MGH再生医学中心的研究人员之间的合作。FHS队列提供了一个大型的、单中心的、以社区为基础的中年和老年人样本，这些人在30年内已被广泛描述，并正在持续监测新发CVD事件。结合研究者的专业知识和良好的表型队列应允许严格检查内皮修复，亚临床CVD和CVD风险之间的关系。身体修复受损血管的能力不足可能会增加患心脏病和中风的风险。如果这一假设是正确的，那么检查血液中的循环“修复”细胞，即内皮祖细胞，可能会深入了解个体对心血管疾病的易感性，并可能提出新的治疗方法。

DESCRIPTION (provided by applicant): Endothelial injury sets in process a chain of events that disrupt vascular homeostasis and promote atherosclerosis. Until recently, it was believed that the endogenous capacity to repair or regenerate damaged endothelium was limited. It is now known that the adult peripheral blood contains a population of endothelial progenitor cells (EPCs) that contribute to vascular repair and re-endothelialization. Early clinical studies raise the possibility that EPCs could serve as a novel biomarker of cardiovascular disease (CVD) risk, but these studies were limited by small sample sizes and lack of longitudinal follow up. We postulate that susceptibility to CVD is determined by the balance between endothelial injury, mediated by CVD risk factors, and endothelial repair, in part determined by EPCs. We propose to test the following hypotheses: (1)'EPC number and function decline with advancing age, and are related to life-long exposure to known CVD risk factors; (2) genetic variation influences EPC measures; (3) reduced EPC number and function are associated with subclinical vascular structural and functional alterations cross-sectionally; and (4) reduced EPC number and function predispose to the development of CVD longitudinally, above and beyond traditional risk factors. We propose to assess EPCs in a large, prospective cohort (approximately 3500 Framingham Heart Study [FHS] participants at Offspring exam 8 and Omni exam 3). Our specific aims are: (1) To examine the clinical and genetic correlates of EPC number and function (using in vitro colony counts, flow cytometry,-migratory assays, and (3-galactosidase staining); (2) To investigate the association of EPC characteristics with subclinical measures of vascular structure (carotid intima-media thickness [IMT], carotid stenosis) and function (peripheral arterial tonometry, brachial flow-mediated dilation, vascular tonometry); and (3) To analyze the relations of EPC characteristics with prevalent and incident CVD. The proposed research represents a collaboration between investigators at the FHS, Massachusetts General Hospital (MGH) Cardiology Division, and MGH Center for Regenerative Medicine. The FHS cohort provides a large, single site, community-based sample of middle-aged and elderly individuals who have been extensively characterized over 3 decades and are under continuous surveillance for new CVD events. The combination of investigator expertise and a well-phenotyped cohort should allow rigorous examination of the relations between endothelial repair, subclinical CVD, and CVD risk. Abnormalities in the body's ability to repair damaged blood vessels may contribute to the risk of heart disease and stroke. If this hypothesis is true, then examination of the circulating "repair" cells in the blood, known as endothelial progenitor cells, may provide insight into an individual's susceptibility to cardiovascular disease and may suggest novel therapeutic approaches.