ENDOTHELIAL PERMEABILITY IN AIRWAY ANGIOGENESIS

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The overall goal of this project is to explore novel ways of targeting endothelial cells at sites of angiogenesis in the respiratory tract. Toward this goal, we will characterize the phenotype of angiogenic endothelial cells, using models of angiogenesis in mice and methods we have developed for studying endothelial cell biology in vivo. The project will take advantage of our recent discovery that angiogenic endothelial cells in vivo internalize cationic liposomes much more avidly than their normal counterparts. The cells also have an abnormal binding pattern to certain plant lectins and are abnormally sensitive to inflammatory mediators that cause plasma leakage. These abnormalities may occur focally at sites of new vessel growth, indicating a hitherto unrecognized heterogeneity of angiogenic endothelial cells. The project will test three hypotheses: First, endothelial cells of angiogenic blood vessels are heterogeneous. Cells at sites of vessel growth are distinctive because of their avid uptake of cationic liposomes, leakiness, and expression of luminal membrane oligosaccharides. Second, the avid uptake of cationic liposomes by angiogenic endothelial cells occurs by receptor-mediated endocytosis. Third, the leakiness of angiogenic endothelial cells is due to an abnormal susceptibility to form intercellular gaps. Our specific aims are to: 1) identify sites of new vessel growth in angiogenic blood vessels and determine whether the endothelial cells at these sites have the distinctive phenotypic features of cationic liposomes, plasma leakage, and abnormal lectin binding; 2) characterize the avid binding and uptake of cationic liposomes to angiogenic endothelial cells, with a focus on receptor- mediated endocytosis; and 3) determine the mechanism of leakiness of angiogenic vessels. The project will take advantage of two models of angiogenesis in mice with which we have had considerable experience. In the first, angiogenesis develops in the airway mucosa as a result of chronic inflammation due to Mycoplasma pulmonis infection. In the other model, angiogenesis occurs in tumors that result from transgenetic expression of the SV-40 viral oncogene. This model provides a way of studying phenotypic changes in angiogenic endothelial cells in a well- characterized progression from normal tissue to tumors. The elucidation of distinctive features of angiogenic endothelial cells and the mechanism of their leakiness to plasma proteins will provide new strategies for targeting and modulating angiogenic blood vessels in the treatment of lung tumors and chronic airway inflammatory diseases such as bronchitis and asthma.