Mechanisms of Coronary Ostium Formation and Coronary Artery Patterning

冠状动脉口形成和冠状动脉模式的机制

• 批准号: 8580415
• 负责人: BIN ZHOU
• 金额: $ 39.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580415
• 关键词: Ablation; Address; Anatomy; Aorta; Binding; Biological Assay; Blood; Blood Circulation; Blood Vessels; Candidate Disease Gene; Cardiac Myocytes; Cells; Clinical; Color; Coronary; Coronary Circulation; Coronary artery; Data; Defect; Development; Diffusion; Embryo; Embryonic Development; Endocardium; Endothelial Cells; Endothelium; Enhancers; Etiology; Genes; Genetic; Genetic Transcription; Goals; Growth; Growth Factor; Heart; Hypoxia; Immunofluorescence Immunologic; Location; Modeling; Molecular; Molecular Analysis; Mus; Muscle Cells; Mutant Strains Mice; Myocardial; Myocardium; Names; Natural regeneration; Nuclear; Nutrient; Outcome; Oxygen; Pathway interactions; Pattern; Pattern Formation; Phase; Phenotype; Process; Reporter Genes; Role; Signal Transduction; Site; Testing; VEGFA gene; Valsalva sinus; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Work; base; cell behavior; heart circulation; hypoxia inducible factor 1; mouse model; nuclear factors of activated T-cells; public health relevance; receptor; spatiotemporal; stem; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): The broad and long-term goal of this project is to understand the patterning of coronary arteries and their underlying mechanisms. The coronary circulation starts when the passive diffusion of oxygen and nutrients is no longer sufficient for the heart growth and function. The coronary arteries must connect to the aorta through the coronary ostia, the openings at the aortic sinus, to receive the oxygenated blood and nutrients from systemic circulation. We have generated new genetic mouse models to study the developmental and molecular mechanisms of the coronary-aorta connection and coronary patterning. Preliminary results have shown that the myocardial vascular endothelial growth factor-a (Vegfa) is necessary for the connection to form. We have also found that the main receptor for Vegfa, Vegfr2, as well as transcription factor Nfatc1 are co- expressed in the aortic sinus endothelium. Additionally, the aortic sinus is surrounding by hypoxic cardiomyocytes that produce a high level of Vegfa. Building upon these findings, this project is to study in mice when and where the myocardial Vegfa is required for the coronary-aorta connection and whether its function is hypoxia-dependent. We will also address whether Vegfr2 and Nfatc1 function together to regulate the connection process. Specifically, we will genetically disrupt Vegfa, Vegfr2, or Nfatc1 in a spatiotemporal manner during late coronary artery development. Ablation of the hypoxic cardiomyocytes or their expression of Vegfa will establish the role of hypoxia in coronary artery patterning and ostium formation. Deletion of Vegfr2 and Nfatc1 in the endocardium of the aortic sinus will ascertain their roles and potential interactions in these processes. Morphologic, cellular, and molecular analysis of the developing coronary arteries and ostia in these mouse mutants will identify previously unknown developmental mechanisms and molecular interactions involved in late coronary artery development. The information will help understand the etiology of congenital coronary anomalies.

描述(由申请者提供)：这个项目的广泛和长期目标是了解冠状动脉的模式及其潜在的机制。当氧气和营养物质的被动扩散不再足以支持心脏的生长和功能时，冠状循环就开始了。冠状动脉必须通过冠状静脉窦的开口与主动脉相连，才能从体循环中获得含氧血液和营养。我们已经建立了新的遗传小鼠模型来研究冠状动脉-主动脉连接和冠状动脉模式的发育和分子机制。初步结果表明，心肌血管内皮生长因子-a(Vegfa)是形成这种连接所必需的。我们还发现，VEGFA的主要受体VEGFR2和转录因子NFATc1在主动脉窦内皮细胞中共表达。此外，主动脉窦周围是低氧心肌细胞，产生高水平的VEGFA。在这些发现的基础上，该项目将在小鼠身上研究冠脉-主动脉连接所需的心肌VEGFa何时何地以及其功能是否依赖于低氧。我们还将讨论VEGFR2和NFATc1是否一起发挥调节连接过程的作用。具体地说，我们将在冠状动脉发育后期以时空方式从基因上干扰Vegfa、VEGFR2或NFATc1。去除缺氧性心肌细胞或其VEGFA的表达将证实低氧在冠状动脉构型和开口形成中的作用。主动脉窦心内膜中VEGFR2和NFATc1的缺失将确定它们在这些过程中的作用和潜在的相互作用。对这些突变小鼠发育中的冠状动脉和吻合口进行的形态、细胞和分子分析将确定以前未知的发育机制和参与冠状动脉发育后期的分子相互作用。这些信息将有助于了解先天性冠状动脉异常的病因。