The Angiopoietins in Vascular Maintenance and Remodeling

血管生成素在血管维护和重塑中的作用

• 批准号: 6623389
• 负责人: Christopher D Kontos
• 金额: $ 34.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623389
• 关键词: Adenoviridae; RNA; angiogenesis; angiogenesis inhibitors; angiopoietins; atherosclerosis; beta galactosidase; blood vessels; enzyme linked immunosorbent assay; gene expression; hyperplasia; jugular veins; laboratory mouse; laboratory rabbit; ligands; microarray technology; northern blottings; protein tyrosine kinase; thrombosis; vascular endothelial growth factors; vascular endothelium; vascular smooth muscle; western blottings

Tie2 is an endothelial receptor tyrosine kinase (RTK) that is required for both embryonic vascular development and pathological angiogenesis. Tie2 is unique among RTKs in that it has two ligands with apparently opposing actions. Angiopoietin-1 (Ang1) is an activating ligand while Angiopoietin-2 (Ang2) is thought to be a naturally occurring antagonist for Tie2. Mice lacking Tie2 or Ang1 die midway through gestation due to abnormalities of vascular morphogenesis characterized by deficient recruitment of supporting smooth muscle cells and pericytes. Moreover, Ang1 promotes endothelial cell survival and blocks the increases in vascular permeability induced by vascular endothelial growth factor (VEGF), supporting a role for Ang1 in the stabilization and maintenance of the adult vasculature. In contrast, Ang2 is required for VEGF-mediated angiogenesis, and in the absence of endothelial mitogens Ang2 may induce vascular regression. The importance of endothelial damage in the progression of vascular diseases has been well documented. Endothelial injury initiates numerous signals that contribute to thrombosis, atherosclerosis, and neointimal hyperplasia. Based on this information, we hypothesize that the Angiopoietins will have differential effects on vascular remodeling; specifically that Ang1, but not Ang2, will prevent endothelial injury-induced vascular remodeling and neointimal hyperplasia. To investigate this hypothesis, the Specific Aims of this proposal are to: 1. Determine the differences in Ang1- and Ang2-mediated gene expression; 2. Develop and characterize specific inhibitors of Ang1 and Ang2; 3. Determine the effects of Ang1 and Ang2 in a venous bypass grafting model; and 4. Determine the effects of inhibiting Ang1 and Ang2 in a venous bypass grafting model. Accomplishing these Specific Aims will provide important insights into the precise roles of the Angiopoietins during maintenance of the adult vasculature and during vascular remodeling, such as that which occurs after venous bypass grafting. Moreover, these studies may lead to the identification of novel therapeutic targets in a variety of vascular diseases.

Tie2 是一种内皮受体酪氨酸激酶 (RTK)，是胚胎血管发育和病理性血管生成所必需的。 Tie2 在 RTK 中是独一无二的，因为它有两个作用明显相反的配体。血管生成素-1 (Ang1) 是一种激活配体，而血管生成素-2 (Ang2) 被认为是 Tie2 的天然拮抗剂。缺乏Tie2或Ang1的小鼠在妊娠中途因血管形态发生异常而死亡，其特征是支持平滑肌细胞和周细胞的募集不足。此外，Ang1 促进内皮细胞存活并阻止血管内皮生长因子 (VEGF) 诱导的血管通透性增加，支持 Ang1 在稳定和维持成人脉管系统中的作用。相反，Ang2 是 VEGF 介导的血管生成所必需的，并且在缺乏内皮细胞有丝分裂原的情况下，Ang2 可能会诱导血管消退。内皮损伤在血管疾病进展中的重要性已得到充分证明。内皮损伤引发大量信号，导致血栓形成、动脉粥样硬化和新内膜增生。基于这些信息，我们假设血管生成素将对血管重塑产生不同的影响；具体来说，Ang1（而非 Ang2）可以预防内皮损伤引起的血管重塑和新内膜增生。为了研究这一假设，本提案的具体目标是： 1. 确定 Ang1 和 Ang2 介导的基因表达的差异； 2. Ang1和Ang2特异性抑制剂的开发和表征； 3.确定Ang1和Ang2在静脉旁路移植模型中的作用； 4.确定在静脉旁路移植模型中抑制Ang1和Ang2的效果。实现这些具体目标将为了解血管生成素在成人脉管系统维持和血管重塑期间（例如静脉旁路移植术后发生的血管重塑）的精确作用提供重要见解。此外，这些研究可能有助于确定多种血管疾病的新治疗靶点。