SPATIAL /TEMPORAL REGULATION OF CORONARY VASCULOGENESIS/ANGIOGENESIS

冠状动脉血管生成/血管生成的空间/时间调节

• 批准号: 6413006
• 负责人: ROBERT J TOMANEK
• 金额: $ 44.31万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6413006
• 关键词: angiogenesis; cardiac myocytes; coronary vessels; developmental genetics; fibroblast growth factor; growth factor; growth factor receptors; histogenesis; laboratory rat; mammalian embryology; newborn animals; nonmammalian vertebrate embryology; platelet derived growth factor; protein localization; quail; vascular endothelial growth factors

(Adapted from the Applicant's Abstract) The overall goal of this project is to elucidate the temporal-spatial and synergistic roles of growth factors in the regulation of events comprising coronary vascularization during heart development. The investigators will conduct (1) in vivo experiments to document the overall temporal-spatial effects of specific growth factors and receptors, and (2) in vitro experiments to determine the effects of growth factors on specific events necessary for vascularization. Both avian (quail) and mammalian (rat) models will be used for protocols which include localizing growth factor protein and mRNA expression, assaying for cell proliferation and migration, and blocking specific growth factors and their receptors. The first aim is to establish the role of these growth factors in the early phase of myocardial vascularization which is dominated by vasculogenesis. Hypotheses to be tested address the roles of the tie-2 receptor and its ligand, angiopoietin-1, and VEGF and bFGF and their receptors. Aim 2 is to determine the growth factors which regulate the subsequent phase of vascularization dominated by sprouting (angiogenesis). The hypotheses focus on (1) VEGF and bFGF as regulators of angiogenesis, (2) local growth factor signaling as a mechanism for guiding endothelial cell cords into the aorta to form the coronary arteries, and (3) the roles of PDGF and bFGF as the primary regulators of smooth muscle migration and assembly into the media of the coronary arteries. Aim 3 will test two hypotheses: (1) hypoxia serves as a metabolic stimulus for the upregulation of VEGF mRNA in embryonic and neonatal cardiomyocytes; (2) stretch of endothelial cells increases their responsiveness to growth factors, and stretch of cardiomyocytes upregulates VEGF and bFGF expression. These studies will demonstrate, for the first time, the temporal-spatial regulation of coronary vessel formation by key growth factors critical to the vascularization cascade. Understanding coronary vasculogenesis and angiogenesis will provide an important foundation for understanding cardiac defects, since myocardial growth is dependent upon timely and adequate vascularization.

（根据申请人的摘要的改编）该项目的总体目标是阐明生长因子在调节心脏发育过程中包含冠状动脉血管化事件的调节中的时间空间和协同作用。 研究人员将进行（1）体内实验，以记录特定生长因子和受体的总体空间效应，以及（2）体外实验，以确定生长因子对血管化所需的特定事件的影响。 禽（鹌鹑）和哺乳动物（大鼠）模型都将用于协议，包括定位生长因子蛋白和mRNA表达，分析细胞增殖和迁移，并阻止特定的生长因子及其受体。 第一个目的是确定这些生长因子在心肌血管的早期阶段的作用，该因子由血管生成主导。要测试的假设解决了TIE-2受体及其配体Angiopoietin-1，VEGF和BFGF及其受体的作用。 目的2是确定调节由发芽（血管生成）主导的血管化阶段的生长因子。 这些假设侧重于（1）VEGF和BFGF作为血管生成的调节剂，（2）局部生长因子信号传导，是将内皮细胞绳引导到主动脉中形成冠状动脉动脉的机制，（3）PDGF和BFGF的作用和BFGF的作用，是固定群体的主要迁移和组装媒体的主要调节器。 AIM 3将检验两个假设：（1）缺氧是胚胎和新生儿心肌细胞中VEGF mRNA上调的代谢刺激； （2）内皮细胞的延伸会增加其对生长因子的反应性，而心肌细胞的拉伸会上调VEGF和BFGF表达。 这些研究将首次证明，通过对血管级联至关重要的关键生长因子对冠状血管形成的时间空间调节。 了解冠状动脉血管生成和血管生成将为理解心脏缺陷提供重要的基础，因为心肌生长取决于及时和适当的血管化。