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: 6565118
• 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: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6565118
• 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.

（改编自申请人摘要）本项目的总体目标是阐明生长因子在心脏发育过程中包括冠状动脉血管形成的事件调节中的时空和协同作用。 研究者将进行（1）体内实验，以记录特定生长因子和受体的总体时空效应，以及（2）体外实验，以确定生长因子对血管形成所需的特定事件的影响。 鸟类（鹌鹑）和哺乳动物（大鼠）模型将用于包括定位生长因子蛋白和mRNA表达、测定细胞增殖和迁移以及阻断特定生长因子及其受体的方案。 第一个目的是建立这些生长因子在心肌血管化的早期阶段，这是占主导地位的血管发生的作用。有待检验的假设涉及tie-2受体及其配体、血管生成素-1、VEGF和bFGF及其受体的作用。 目的2是确定生长因子，调节随后阶段的血管化为主的发芽（血管生成）。 这些假说集中在（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作为引导内皮细胞索进入主动脉形成冠状动脉的机制，和（3）PDGF和bFGF作为平滑肌迁移和组装进入冠状动脉介质的主要调节剂的作用。 目的3将验证两个假设：（1）缺氧作为一种代谢刺激因子，促进胚胎和新生心肌细胞VEGF mRNA的上调;（2）内皮细胞的牵张增加了它们对生长因子的反应性，心肌细胞的牵张上调VEGF和bFGF的表达。 这些研究将首次证明，冠状动脉血管形成的时间-空间调节的关键生长因子的血管级联反应。 了解冠状动脉血管发生和血管生成将为了解心脏缺陷提供重要基础，因为心肌生长依赖于及时和充分的血管化。