Angiopoietins in airway vascular leak and angiogenesis

描述(申请人提供)：本项目的续签将审查 新近发现的血管内皮细胞家族--血管生成素的作用 细胞特异性生长因子对血管渗漏和血管重塑的影响 在呼吸道炎症中。该项目将建立在 血管生成素-1(Ang1)减少这笔赠款的头两年半 多种不同炎症介质引起的血浆渗漏。Ang1也 触发呼吸道粘膜中小静脉的扩大，但不会在其他地方 身体。这些作用是由Tie2酪氨酸激酶受体介导的 在内皮细胞上，与大量渗漏血的形成形成对比 另一种血管内皮细胞--血管内皮生长因子(血管内皮生长因子) 细胞特异性生长因子。该项目将检验总体假设，即 大鼠血浆漏出量与微血管重构类型的关系 慢性呼吸道疾病由生长因子的平衡决定，如 血管紧张素-1和血管内皮生长因子作用于血管系统。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大小 血管紧张素转换酶1对呼吸道血管的渗漏作用。我们的假设是，这是 血管紧张素转换酶1的作用是通过抑制血管内皮细胞缝隙的形成 维管壁和细胞间连接的稳定。(2)第二，我们将 观察血管紧张素转换酶1诱导的呼吸道微血管重构。这里, 假设是Ang1增加了呼吸道内小静脉的口径。 粘膜上高密度的Tie2受体在这些血管上偶联 血管紧张素转换酶1对血管内皮细胞的作用 本质上是动态的血管系统。(三)三是制定更加完善的 血管紧张素转换酶1和血管内皮生长因子在微血管渗漏中的相互作用 和血管生成。这些实验将检验这样一个假设，即Ang1可以 在不阻断血管生成的情况下减少血管内皮生长因子诱导的血管渗漏。这些研究 还将讨论Ang1是否可以使结构正常化的问题 血管生成血管对血管内皮细胞生长因子的稳定作用 成熟管壁，加强细胞间连接。这个 研究计划提供了洞察关键增长因素的机会 参与血管通透性和血管重塑的调节 呼吸道发炎。进一步阐明Ang1的保护作用 关于血管泄漏的研究将增加一种新战略的可能性 减少慢性炎症性疾病(如支气管炎和肺炎)的呼吸道水肿 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.