The process of systemic angiogenesis in the lung remains poorly understood despite it being an integral part of a wide range of human diseases including asthma, COPD, cystic fibrosis, lung cancer, and chronic thromboembolism. Despite the importance and prevalence of this systemic vascular remodeling, methods to study the process in humans are not feasible, and few animal models exist. Thus, the proposed model of left pulmonary artery occlusion in the mouse provides a unique opportunity to study the mechanisms of systemic neovascularization in the lung. The experiments proposed in this application will determine the initiating signals and the essential inflammatory cells and cytokines in promoting new vessel growth. Our data demonstrate that an increase in the number of inflammatory cells in the lung appears to play a major role in directing neovascularization. However, the factors that initiate leukocyte activation and the cascade of events that promote new vessel growth are not known. Obstruction of the left pulmonary artery results in a loss of shear stress, relative hyperoxia, and decreased glucose supply, all of which contribute to an increase in oxidative stress. Several studies have shown oxidant-dependent activation of monocytes/macrophages. Additionally, reactive oxygen species (ROS) have been shown to cause lung matrix degradation, the products of which are known to activate macrophages through Toll-like receptors (TLR). Our preliminary work demonstrates, 1) that inhibition of ROS limits angiogenesis, 2) that there is an increase in matrix fragmentation coincident with ROS release, 3) that TLR-2 modulates angiogenic outcome, and 4) that the number of lavaged macrophages are predictive of the magnitude of the angiogenic response. These experiments led us to hypothesize that ROS, released from ischemic pulmonary endothelium, stimulate lung monocytes/macrophages to release pro- angiogenic growth factors that induce systemic vascularization of the lung. We predict both direct activation of monocytes by ROS as well as indirect activation by lung matrix components. We will use the established, in vivo mouse model of lung angiogenesis after left pulmonary artery ligation to determine cellular and molecular mechanisms of neovascularization. We will focus on three specific aims to measure and determine that 1) ROS release by pulmonary endothelium is essential for systemic angiogenesis, 2) ROS activate lung monocytes/macrophages to a pro-angiogenic phenotype, and 3) monocyte/macrophage-derived growth factors are essential for systemic angiogenesis. We will use oxidant-sensitive dyes to measure ROS, evaluate differentiation/proliferation of monocytes, and perfusion of the systemic vasculature to the lung by labeled microspheres, in mice without/with antioxidant enzymes/treatments. The results of this project will allow us to determine how ROS-induced activation of monocytes promotes systemic neovascularization.
Excessive systemic vascular proliferation occurs in many pulmonary diseases such as asthma, cystic fibrosis, and chronic thromboembolism where inflammation, edema, and hemoptysis contribute to lung pathology. The mechanisms responsible for the growth of new vessels are not understood. In an animal model of chronic pulmonary thromboembolic disease, this project will determine the inflammatory cytokines and cells responsible for new vessel growth, and pharmacological and interventional inhibitors.
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