Angiopoietins in airway vascular leak and angiogenesis

描述（由申请人提供）：该项目的更新将审查 血管生成素（最近发现的内皮细胞家族）的作用 细胞特异性生长因子对血管渗漏和血管重塑的影响 气道炎症该项目将建立在 在这项资助的前两年半，血管生成素-1（Ang1）降低了 由多种不同的炎症介质引起的血浆渗漏。Ang1 触发气道粘膜中的小静脉扩大，但不会在 身体这些作用由Tie2酪氨酸激酶受体介导， 在内皮细胞上，与大量漏血的形成相反， 血管内皮生长因子（VEGF），另一种内皮 细胞特异性生长因子该项目将测试总体假设， 血浆渗漏量和微血管重塑类型 慢性气道疾病是由生长因子的平衡决定的， Ang1和VEGF作用于血管系统。该项目有三个具体目标。 (1)首先，我们将确定抗血浆的机制和幅度 Ang1对气道血管的渗漏作用。我们的假设是 Ang1的作用是通过以下途径抑制内皮间隙的形成 血管壁和细胞间连接的稳定。(2)二是 检查Ang1诱导的气道微血管重塑。在这里， 假设血管生成素1增加气道小静脉的口径 由于这些血管上的Tie2受体的高密度， Ang1对内皮细胞的存活因子作用 内在动态的脉管系统。(3)第三，我们将制定一个更完整的 了解Ang1和VEGF在微血管渗漏中的相互作用 和血管生成。这些实验将验证Ang1可以 减少VEGF诱导的血管渗漏而不阻断血管生成。研究 还将解决Ang1是否可以正常化结构的问题， 功能的血管生成血管形成的VEGF的反应，通过稳定 并使血管壁成熟和加强细胞间连接。的 研究计划提供了深入了解关键增长因素的机会 参与调节血管通透性和血管重塑， 气道炎症此外，阐明Ang1的保护作用 血管渗漏的可能性将提高一个新的战略， 减少慢性炎性疾病如支气管炎的气道水肿， 哮喘

DESCRIPTION (provided by applicant): The renewal of this project will examine the effects of angiopoietins, a recently discovered family of endothelial cell-specific growth factors, on blood vessel leakiness and vascular remodeling in airway inflammation. The project will build on the discovery made during the first two and a half years of this grant that angiopoietin-1 (Ang1) reduces plasma leakage evoked by multiple different inflammatory mediators. Ang1 also triggers the enlargement of venules in the airway mucosa but not elsewhere in the body. These actions, which are mediated by Tie2 tyrosine kinase receptors on endothelial cells, contrast with the formation of abundant leaky blood vessel by VEGF (vascular endothelial growth factor), another endothelial cell-specific growth factor. The project will test the overall hypothesis that the amount of plasma leakage and the type of microvascular remodeling in chronic airway disease are determined by the balance of growth factors such as Ang1 and VEGF acting on the vasculature. The project has three specific aims. (1) First, we will determine the mechanism and magnitude of the anti-plasma leakage effect of Ang1 on airway blood vessels. Our hypothesis is that this action of Ang1 results from the inhibition of endothelial gap formation through stabilization of vessel walls and intercellular junctions. (2) Second, we will examine Ang1-induced remodeling of the microvasculature in the airways. Here, the hypothesis is that Ang1 increases the caliber of venules in the airway mucosa because of the high density of Tie2 receptors on these vessels coupled with the survival factor action of Ang1 on endothelial cells of this intrinsically dynamic vasculature. (3) Third, we will develop a more complete understanding of the interplay between Ang1 and VEGF on microvascular leakage and angiogenesis. These experiments will test the hypothesis that Ang1 can reduce VEGF-induced vessel leakiness without blocking angiogenesis. The studies will also address the question of whether Ang1 can normalize the structure and function of angiogenic blood vessels formed in response to VEGF by stabilizing and maturing the vessel wall and strengthening intercellular junctions. The research plan provides an opportunity to gain insight into key growth factors involved in the regulation of vascular permeability and vascular remodeling in airway inflammation. Furthermore, elucidation of the protective effect of Ang1 on blood vessel leakiness would raise the possibility of a new strategy for reducing airway edema in chronic inflammatory diseases such as bronchitis and asthma.