Mechanisms of endothelial repair after vascular injury

血管损伤后内皮修复机制

基本信息

批准号：
8312394
负责人：
Zvonimir S Katusic
金额：
$ 37.4万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8312394
关键词：
Aging Anabolism Arachidonic Acids Area Blood Blood Vessels Bone Marrow Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Characteristics Common carotid artery Development Drug Delivery Systems Employee Strikes Endothelium Epoprostenol Epoprostenol Receptors Genetic Goals Health Human Human Characteristics In Vitro Injury Ischemia Laboratories Limb structure Literature Metabolism Modeling Modification Molecular Myocardial Infarction Nude Mice Pathway interactions Prevention approach Prevention therapy Prostacyclin synthase Prostaglandin-Endoperoxide Synthase Prostaglandins Prostaglandins I Protein Isoforms Regulation Role Safety Stem cells Stimulus Stroke Testing Therapeutic Time Tissues Vascular Endothelium age effect aged angiogenesis base in vivo inattention inhibitor/antagonist injured insight novel novel therapeutic intervention regenerative repaired research study response volunteer

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop novel endothelium-targeted therapies for the prevention and treatment of cardiovascular disease. Discovery of circulating endothelial progenitor cells (EPCs) revolutionized understanding of the mechanisms responsible for endothelial repair after vascular injury and revascularization of ischemic tissues. However, the mechanisms underlying beneficial effects of EPCs are poorly understood. Prostacyclin (PGI2) is one of the most important vasoprotective molecules released from vascular endothelium. Strikingly, the role of arachidonic acid metabolism and biosynthesis of PGI2 in regulation of regenerative function of EPCs has not been studied. In our preliminary studies we identified intrinsically high biosynthesis of PGI2 as one of the major phenotypic characteristics of human EPCs. Furthermore, our studies indicate that pharmacological or genetic inactivation of PGI2 significantly impairs regenerative capacity of EPCs. Therefore, the general hypothesis of this application is that in the cardiovascular system, biosynthesis of PGI2 in EPCs is an essential mechanism responsible for the regenerative function of EPCs. To test this hypothesis we propose studies with the following specific aims: 1) determine expression and function of cyclooxygenase (COX) isoforms and profile of prostanoids biosynthesis in human EPCs, 2) define the role of PGI2 in regenerative functions of EPCs, and 3) analyze the role of arachidonic acid metabolism in aging-induced decline in regenerative capacity of EPCs. Experiments will be performed on EPCs isolated from circulating blood of healthy young and aged volunteers. The role of EPCs-derived PGI2 in repair injured endothelium or angiogenesis will be studied in vitro and in vivo. Established models of wire-induced injury of common carotid artery and hind limb ischemia in nude mice will be employed to determine the role of PGI2 derived from EPCs in endothelial repair and revascularization. Genetic modification of human EPCs will be carried out to gain further mechanistic insight into the role of arachidonic acid metabolism in reparative functions and aging of EPCs. The proposed studies will provide currently missing information regarding the role of prostanoids released from EPCs in response of the cardiovascular system to injury and aging. Understanding of these mechanisms will establish basis for development of novel therapeutic approaches to prevention and treatment of cardiovascular diseases. PUBLIC HEALTH RELEVANCE: Project Narrative Endothelial Progenitor Cells (EPCs) are released from the bone marrow during cardiovascular diseases including myocardial infarction and stroke. Their major function is to repair injured blood vessels and restore normal cardiovascular function. Currently, efforts of many laboratories, including ours, are focused on understanding the mechanisms responsible for regenerative function of EPCs. The long-term goal of this application is to harness therapeutic potential of EPCs.

描述（由申请人提供）：该项目的长期目标是开发新型的内皮靶向疗法，以预防和治疗心血管疾病。发现循环内皮祖细胞（EPC）的发现彻底改变了对血管损伤和缺血组织血运重建后负责内皮修复机制的理解。但是，EPC的有益作用的基础机制知之甚少。前列环蛋白（PGI2）是从血管内皮释放的最重要的血管保护分子之一。令人惊讶的是，尚未研究蛛网膜酸代谢和PGI2的生物合成在EPCS再生功能调节中的作用。在我们的初步研究中，我们将PGI2的本质上高生物合成确定为人类EPC的主要表型特征之一。此外，我们的研究表明，PGI2的药理学或遗传失活会严重损害EPC的再生能力。因此，该应用的一般假设是在心血管系统中，EPC中PGI2的生物合成是负责EPC再生功能的基本机制。为了检验该假设，我们提出了以下特定目的的研究：1）确定环氧酶（COX）同工型的表达和功能和前列腺素的生物合成在人EPC中的生物合成的谱，2）定义PGI2在EPCS的再生功能中的作用，以及3）分析了Arachidonic酸的作用。实验将对从健康的年轻和老年志愿者的循环血液中分离出来的EPC进行。 EPCS衍生的PGI2在维修受伤的内皮或血管生成中的作用将在体外和体内研究。将采用固定的颈动脉和后肢缺血的线诱导的裸鼠损伤模型，以确定源自EPC的PGI2在内皮修复和血运重建中的作用。将进行人类EPC的遗传修饰，以进一步洞悉蛛网膜酸代谢在修复功能和EPC衰老中的作用。拟议的研究将提供目前缺少有关EPCS在心血管系统响应损伤和衰老中释放前列腺素的作用的信息。对这些机制的理解将为开发新型治疗方法的预防和治疗心血管疾病的基础。公共卫生相关性：项目叙事内皮祖细胞（EPC）在心血管疾病中从骨髓中释放出来，包括心肌梗塞和中风。他们的主要功能是修复受伤的血管并恢复正常的心血管功能。当前，许多实验室（包括我们的实验室）的努力集中在理解负责EPC再生功能的机制上。该应用的长期目标是利用EPC的治疗潜力。