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.
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